Biomimetic total synthesis of resorcylate natural products via a decarboxylative, allyl migration and aromatisation sequence

Angelico in A (I), angelicoin B (II), cristatic acid (III) and grifolic acid (IV) (Figure A1) are members of the resorcylate family of natural products which contain a common 6-alkyl-2,4-dihydroxy benzoic acid core (β-resorcylate unit). The total syntheses of angelicoin A (I) and angelicoin B (II) from 2,2,6-trimethyl-4H-1,3-dioxin-4-one V are reported using late stage aromatisation reactions via diketo-dioxinones as advanced intermediates. In the case of angelicoin A (I), biomimetic aromatisation was coupled with a highly regioselective palladium(0)-catalysed decarboxylative prenyl migration as the key step (Scheme A1).(a)(b) The palladium(0)-catalysed decarboxylative, prenylation and aromatisation sequence furnished both linear VII and branched adducts VI. Extensive optimisation of conditions to improve the ratio of linear to branched adducts involved the screening of palladium catalysts, ligands, solvents, reactions times, temperature and organic and inorganic bases.(a)(c) The regioselectivity of this novel palladium(0)- catalysed decarboxylative prenyl migration was determined unambiguously through X-ray crystallographic studies.(a)(c) Furthermore, an intermolecular mechanism is proposed after thorough mechanistic studies including cross over and variable concentration experiments, base studies and regioselectivity investigations. Two synthetic approaches towards the total synthesis of cristatic acid methyl ester are reported. The first approach investigated a one-pot reaction to install the furan moiety VIII (Scheme A2), via a Nef reaction, deprotection, decarboxylation and furan formation. The second approach attempted to perform a one-pot Pd(0)-decarboxylative allylation, TMSE deprotection and aromisation to provide the core of cristatic acid IX (Scheme A3). Finally, studies towards the total synthesis of grifolic acid (IV) are reported utilising the palladium(0)-catalysed decarboxylative allyl migration and aromatisation sequence.Open Acces

Civilizing suburbia

Thesis (M.Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 2000.Includes bibliographical references (p. 33).When I began my study of architecture ten years ago, I honestly believed that architecture could change the world. As I look back at how the American landscape has changed since then I realize that architecture has changed the world, but not necessarily in the way I imagined. As our population has grown architecture has reflected the increasing emphasis on consumerism, a decreased interest in public life and even less interest in the natural environment. Consequently terms like suburban sprawl have adequately been coined to describe the spreading wave of decentralized settlement that characterizes our landscape. Even though over 80% of the new homes schools and shopping facilities are now located in the suburbs, many designers still do not consider the suburbs to be within the field of architectural practice. I do not hold to this view and believe that this is where architecture can make the biggest difference and where the greatest opportunity for architects to shape the world may be found. What defines architecture today is not just a question of good or bad aesthetics, but is how the design impacts our culture. With each building, landscape or urban plan we create we have the opportunity to reinforce current values or to establish new values which can lead us to explore more sustainable solutions. This thesis looks at a site in suburban Miami and demonstrates how we can redirect our growth toward the protection of our natural resources and contribute important public space that celebrates the value of our environment.Katie Elizabeth Anderson.M.Arch

Resonance in Human Walking Economy: How Natural Is It?

Locomotion and movement economy are cornerstone topics in movement science. Modeling the leg as a hybrid mass-spring pendulum shows walking economy should be optimized when stride frequency matches the resonant frequency of the limb. Human walking is described as self-optimizing because mean preferred (PSF) and modeled resonant (RSF) stride frequencies usually are statistically equivalent, but this depiction may not be fully justified. Purpose: To more thoroughly examine the self-optimization characterization and the consequences of obligating use of the RSF. Methods: Forty-seven individuals of diverse statures completed 3 consecutive days of preferred walking trials on a treadmill where stride rate, stride length, walking speed, heart rate and walking economy measures were made under steady state heart rate conditions. Anthropometric measures were taken to build a hybrid model of the leg and model the RSF. Reliability across days was evaluated via repeated measures analysis of variance (ANOVA) and intra-class correlation (á=.05) and correlations were calculated for PSF and RSF. A separate sample of 20 participants walked under 3 conditions, (1) completely preferred; (2) at the original preferred speed using the RSF; and (3) with the option to establish a new preferred speed while using the RSF. Results: Gait characteristics were fundamentally reliable across days and the correlation between PSF and RSF was weak (8% explained variance). Walking economy improved 14% when using the RSF and allowed to self-select the speed / stride length used at that cadence. Conclusions: The results raised slight questions about current self-optimization presumptions and further emphasized the role of resonance in walking economyFaculty Sponsor: Dr. Philip K. Scho

Frequency of Vending Machine Usage as a Predictor of Weight Status Among College Students

Background: College students have identified frequent unhealthy snacking from vending machines as influencing their dietary intake and weight status. However, research on associations between vending usage and weight status is lacking. Objectives: 1.) Compare college students’ demographic characteristics by frequency of vending machine usage (FVU) and body mass index (BMI). 2.) Determine associations between FVU and BMI levels among college students. Methods: Using a cross-sectional study design, a convenience sample of college students (n=110) completed an online survey providing demographics, height and weight, and FVU – categorized as “none” (never or rarely), “low” (less than once per month, or “high” (once per month or more). Demographics were analyzed using descriptive statistics with comparisons by FVU and BMI levels. Associations between FVU and BMI levels, alone and controlling for sex and race/ethnicity, were tested using a proportional odds logistic model. Results: The majority of participants were in the lowest FVU (50%) and normal BMI (56%; M=24.2 kg/m2) levels. BMI was significantly different by FVU levels (p=.012). Logistic regression indicated the highest FVU category was associated with a 4.6 times greater odds of being overweight or obese (p=0.001). Conclusion: This study described a significant relationship between higher levels of FVU and higher levels of BMI among college students. This formative evidence can inform future vending interventions in this population

Examination of near-wall hemodynamic parameters in the renal bridging stent of various stent graft configurations for repairing visceral branched aortic aneurysms

ObjectiveThis study examined the flow behavior of four stent graft configurations for endovascular repair of complex aneurysms of the descending aorta.MethodsComputational fluid dynamics models with transient boundary conditions and rigid wall simplifying assumptions were developed and used with four distinct geometries to compare various near-wall hemodynamic parameters.ResultsGraphic plots for time-averaged wall shear stress, oscillating shear index, and relative residence time were presented and compared among the four stent graft configurations of interest.ConclusionsAbrupt 90° and 180° changes in stent geometry (particularly in the side branches) cause a high momentum change and thus increased flow separation and mixing, which has significant implications in blood flow characteristics near the wall. By comparison, longer bridging stents provide more gradual changes in momentum, thus allowing blood flow to develop before reaching the target vessel.Clinical RelevanceRenal vessel patency is a well-known but rarely talked about challenge with complex aneurysm repair. Many factors need to be optimized to ensure branch vessel patency in aneurysms of the visceral segment, including bridging stent compliance transition, bridging stent material selection and design, and main body graft alignment. One topic that has not been discussed much is the flow characteristics entering the branch. Here we propose a technique to evaluate device configurations and their associated flows for their ability to maintain branch vessel patency

Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

Longitudinal assessment of cognitive and psychosocial functioning after Hurricanes Katrina and Rita: Exploring disaster impact on middle-aged, older, and oldest-old adults

The authors examined the effects of Hurricanes Katrina and Rita on cognitive and psychosocial functioning in a lifespan sample of adults 6-14 months after the storms. Participants were recruited from the Louisiana Healthy Aging Study. Most were assessed during the immediate impact period and retested for this study. Analyses of pre- and post-disaster cognitive data confirmed that storm-related decrements in working memory for middle-aged and older adults observed in the immediate impact period had returned to pre-hurricane levels in the post-disaster recovery period. Middle-aged adults reported more storm-related stressors and greater levels of stress than the two older groups at both waves of testing. These results are consistent with a burden perspective on post-disaster psychological reactions. © 2012 Wiley Periodicals, Inc

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs