Studies Toward the Total Synthesis of Hinckdentine A using Under Utilised Reactions and Functional Groups

Many useful organic transformations remain underutilised because they have not been thoroughly investigated and understood. We have sought to expand the utility of neglected reactions and functional groups by investigating their mechanism and examining their scope. We planned to demonstrate utility of these transformations by incorporating them as key steps in the total synthesis of the natural product hinckdentine A. We developed a rational and consistent theory for mechanism of on-water catalysis. This new theory has allowed us to identify previously unrecognised examples of this phenomenon. The traditionally difficult conjugate addition of anilines was found to be facile under on-water conditions and this reaction was further improved through the incorporation of N-acylpyrroles. N-Acylpyrroles were also found to facilitate the Stetter reaction and expand the scope of subsequent transformations. The understanding gained from these studies allowed us to undertake studies toward the total synthesis of hinckdentine A, by an innovative route which included the aforementioned reactions as integral transformations

Identification of β2-adrenoceptors on guinea pig alveolar macrophages using (-)-3-[125I]iodocyanopindolol

The β-adrenoceptor antagonist (-)-3-[125I]iodocyanopindolol ([125I]ICYP) binds with high affinity and in a saturable way to membranes of guinea pig alveolar macrophages. The equilibrium dissociation constant for [125I]ICYP is 24.3 ± 1.2 pM, and the number of binding sites is 166.3 ± 13.7 fmol/mg protein (N=4, ±SEM). Displacement studies with selective antagonists showed that [125I]ICYP labels β2-adrenoceptors on guinea pig alveolar macrophages

Pulmonary granulocyte influx and impaired alveolar macrophage adenylyl cyclase responsiveness in developing respiratory distress

Alveolar macrophages have recently been postulated as being involved in the aetiology of adult respiratory distress syndrome (ARDS). To evaluate their role, basal cyclic AMP levels and responsiveness of adenylyl cyclase alveolar macrophages were determined at four intermediate stages of developing respiratory distress in piglets using a protocol with repeated lung lavage. Examination of alveolar cells recovered from the subsequent lavages reveals an influx of granulocytes (neutrophils and eosinophils) within 1 h of two intensive lung lavages. During the developing respiratory distress the basal cyclic AMPlevel of alveolar macrophages increases and adenylyl cyclase responsiveness to prostaglandin E2 (PGE2) and isoprelanaline diminishes. The previously observed impairment of macrophage activity can then be explained at a subcellular level

Understanding the effect of an educational intervention to optimize HIV testing strategies in primary care in Amsterdam - results of a mixed-methods study.

BACKGROUND: In the Netherlands, general practitioners (GPs) play a key role in provider-initiated HIV testing, but opportunities for timely diagnosis are regularly missed. We implemented an educational intervention to improve HIV testing by GPs from 2015 to 2020, and observed a 7% increase in testing in an evaluation using laboratory data. The objective for the current study was to gain a deeper understanding of whether and how practices and perceptions of GPs' HIV/sexually transmitted infection (STI) testing behaviour changed following the intervention. METHODS: We performed a mixed-methods study using questionnaires and semi-structured interviews to assess self-reported changes in HIV/STI testing by participating GPs. Questionnaires were completed by participants at the end of the final educational sessions from 2017 through 2020, and participating GPs were interviewed from January through March 2020. Questionnaire data were analysed descriptively, and open question responses were categorised thematically. Interview data were analysed following thematic analysis methods. RESULTS: In total, 101/103 participants completed questionnaires. Of 65 participants that were included in analyses on the self-reported effect of the programme, forty-seven (72%) reported it had changed their HIV/STI testing, including improved STI consultations, adherence to the STI consultation guideline, more proactive HIV testing, and more extragenital STI testing. Patients' risk factors, patients' requests and costs were most important in selecting STI tests ordered. Eight participants were interviewed and 15 themes on improved testing were identified, including improved HIV risk-assessment, more proactive testing for HIV/STI, more focus on HIV indicator conditions and extragenital STI testing, and tools to address HIV during consultations. However, several persistent barriers for optimal HIV/STI testing by GPs were identified, including HIV-related stigma and low perceived risk. CONCLUSIONS: Most GPs reported improved HIV/STI knowledge, attitude and testing, but there was a discrepancy between reported changes in HIV testing and observed increases using laboratory data. Our findings highlight challenges in implementation of effective interventions, and in their evaluation. Lessons learned from this intervention may inform follow-up initiatives to keep GPs actively engaged in HIV testing and care, on our way to zero new HIV infections

Infant mortality in mid-19th century Amsterdam:Religion, social class, and space

This study uses a unique historical GIS dataset compiled from birth, death, and population register records for infants born in the city of Amsterdam in 1851 linked to micro‐level spatial data on housing, infrastructure, and health care. Cox's proportional hazards models and the concept of egocentric neighbourhoods were used to analyse the effects of various sociodemographic characteristics, residential environment, water supply, and health‐care variables on infant mortality and stillbirth. The analyses confirm the favourable position of the Jewish population with respect to infant mortality as found in other studies and show the unfavourable position of orthodox Protestant minorities. Infant mortality rate differences are much smaller between social classes than between religions. The exact role of housing and neighbourhood conditions vis‐a‐vis infant mortality is still unclear; however, we ascertained that effects of environmental conditions are more pronounced in later stages of infancy and less important in the early stages of infancy

Stimulation of cyclic AMP production in human alveolar macrophages induced by inflammatory mediators and β-sympathicomimetics

Abstract We have investigated the effects of inflammatory mediators and β-adrenoceptor agonists on the adenylyl cyclase responsiveness in alveolar macrophages from control subjects, patients suffering from chronic obstructive pulmonary disease (COPD) and asthmatics. Basal cyclic AMP (cAMP) levels in alveolar macrophages from COPD patients were significantly elevated (plus 42%) as compared to controls. In addition, the adenylyl cyclase responsiveness to prostaglandin E2, histamine and the β-adrenoceptor agonist salbutamol was significantly impaired in alveolar macrophages from COPD patients and asthmatics. The lipid mediator platelet activating factor showed no effect on cAMP production in all three alveolar macrophage populations. Furthermore, the cAMP-enhancing effects of isoprenaline, salbutamol and histamine appeared to be mediated via β2-adrenoceptors and histamine H2-receptor subtypes respectively. Taken together, these data suggest an intrinsic desensitization phenomenon in alveolar macrophages from COPD patients and asthmatics

The risks of risk assessment: causal blind spots when using prediction models for treatment decisions

Prediction models are increasingly proposed for guiding treatment decisions, but most fail to address the special role of treatments, leading to inappropriate use. This paper highlights the limitations of using standard prediction models for treatment decision support. We identify `causal blind spots' in three common approaches to handling treatments in prediction modelling: including treatment as a predictor, restricting data based on treatment status and ignoring treatments. When predictions are used to inform treatment decisions, confounders, colliders and mediators, as well as changes in treatment protocols over time may lead to misinformed decision-making. We illustrate potential harmful consequences in several medical applications. We advocate for an extension of guidelines for development, reporting and evaluation of prediction models to ensure that the intended use of the model is matched to an appropriate risk estimand. When prediction models are intended to inform treatment decisions, prediction models should specify upfront the treatment decisions they aim to support and target a prediction estimand in line with that goal. This requires a shift towards developing predictions under the specific treatment options under consideration (`predictions under interventions'). Predictions under interventions need causal reasoning and inference techniques during development and validation. We argue that this will improve the efficacy of prediction models in guiding treatment decisions and prevent potential negative effects on patient outcomes

Comparison of haemodynamic- and electroencephalographic-monitored effects evoked by four combinations of effect-site concentrations of propofol and remifentanil, yielding a predicted tolerance to laryngoscopy of 90%

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (Ce-PROP) and remifentanil (Ce-REMI), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (P-TOL = 90%) according to the Bouillon interaction model. We aimed to identify combinations of Ce-PROP and Ce-REMI along a single isobole of P-TOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards Ce-PROP (Schnider model, ug.ml(-1)) and Ce-REMI (Minto model, ng.ml(-1)) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with Ce-PROP. Heart rate decreased with increasing Ce-REMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but Ce-PROP = 3.6 mu g.ml(-1) and Ce-REMI = 4 ng.ml(-1) evoked the lowest median value for increment HR and increment SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted P-TOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for P-TOL, suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted P-TOL must be considered preliminary because larger numbers of observations are required for that goal