Development of Pd Catalyzed Amidations & Applications to the Synthesis of Heterocycles

Chapter 1 A brief overview of C-N amide bond formation: past methods and current catalytic approaches. Chapter 2 A facile synthesis of imidazo[4,5-b]pyridines and -pyrazines is described using a Pd-catalyzed amide coupling reaction. This reaction provides quick access to products with substitution at N1 and C2. A model system relevant to the natural product pentosidine has been demonstrated, as well as the total synthesis of the mutagen 1-Me-5-PhIP. This reaction was then further explored to utilize more readily available catalytic components and to increase the substrate and amide scope. Chapter 3 The C2 amination of imidazo[4,5-b]pyridines was accomplished through C2 halogenation followed by substitution (SNAr) with functionalized primary and secondary amines. This regioselective sequence is operationally simple and provides an easy access to derivatives of protected imidazo[4,5-b]pyridines. Chapter 4 Pentosidine, a biologically important advanced glycation endproduct, has been accessed in a rapid, high-yielding manner. The synthesis was accomplished via a six-step sequence starting with 3-amino-2-chloropyridine and features a palladium-catalyzed tandem cross-coupling/cyclization to construct the imidazo[4,5-b]pyridine core. Chapter 5 A copper catalyzed amidation of Boc protected 4-chloro-3-aminopyridine was accomplished to produce a number of aryl and heteroaryl 4-chloro-3-aminopyridines. These pyridines were used to synthesize regioselectively substituted imidazo[4,5-c]pyridines using a Pd-catalyzed amide coupling reaction. Chapter 6 A regioselective palladium-catalyzed amidation of polychlorinated aminopyridines was accomplished to provide chlorinated imidazo[4,5-b]pyridines. A preliminary optimization of these reaction conditions is described herein

Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy.

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO

Narrative descriptions should replace grades and numerical ratings for clinical performance in medical education in the United States

Background: In medical education, evaluation of clinical performance is based almost universally on rating scales for defined aspects of performance and scores on examinations and checklists. Unfortunately, scores and grades do not capture progress and competence among learners in the complex tasks and roles required to practice medicine. While the literature suggests serious problems with the validity and reliability of ratings of clinical performance based on numerical scores, the critical issue is not that judgments about what is observed vary from rater to rater but that these judgments are lost when translated into numbers on a scale. As the Next Accreditation System of the Accreditation Council on Graduate Medical Education (ACGME) takes effect, medical educators have an opportunity to create new processes of evaluation to document and facilitate progress of medical learners in the required areas of competence. Proposal and initial experience: Narrative descriptions of learner performance in the clinical environment, gathered using a framework for observation that builds a shared understanding of competence among the faculty, promise to provide meaningful qualitative data closely linked to the work of physicians. With descriptions grouped in categories and matched to milestones, core faculty can place each learner along the milestones' continua of progress. This provides the foundation for meaningful feedback to facilitate the progress of each learner as well as documentation of progress toward competence. Implications: This narrative evaluation system addresses educational needs as well as the goals of the Next Accreditation System for explicitly documented progress. Educators at other levels of education and in other professions experience similar needs for authentic assessment and, with meaningful frameworks that describe roles and tasks, may also find useful a system built on descriptions of learner performance in actual work settings. Conclusions: We must place medical learning and assessment in the contexts and domains in which learners do clinical work. The approach proposed here for gathering qualitative performance data in different contexts and domains is one step along the road to moving learners toward competence and mastery

Progress Towards the Total Synthesis of 3α-Hydroxy-15-Rippertene

The Rh(I)-catalyzed allenic cyclocarbonylation reaction is a formal [2 + 2 + 1] cyclocarbonylation process that has been used to gain access to 4-alkylidenecyclopentenones. Inclusion of a six-membered ring on the tether between the allene and the alkyne components allows access to a variety of [6-7-5] ring structures found in the core-skeletons of natural products such as rippertene. This thesis describes a synthetic approach to the carbocyclic skeleton of 3α-hydroxy-15-rippertene, utilizing the Rh(I)-catalyzed allenic cyclocarbonylation reaction. Starting from 2-butyn-1-ol the [6-7-5] carbocyclic core of rippertene was synthesized in 1.9% over 10 steps

Bringing new tools, a regional focus, resource-sensitivity, local engagement and necessary discipline to mental health policy and planning

Background: While reducing the burden of mental and substance use disorders is a global challenge, it is played out locally. Mental disorders have early ages of onset, syndromal complexity and high individual variability in course and response to treatment. As most locally-delivered health systems do not account for this complexity in their design, implementation, scale or evaluation they often result in disappointing impacts. Discussion: In this viewpoint, we contend that the absence of an appropriate predictive planning framework is one critical reason that countries fail to make substantial progress in mental health outcomes. Addressing this missing infrastructure is vital to guide and coordinate national and regional (local) investments, to ensure limited mental health resources are put to best use, and to strengthen health systems to achieve the mental health targets of the 2015 Sustainable Development Goals. Most broad national policies over-emphasize provision of single elements of care (e.g. medicines, individual psychological therapies) and assess their population-level impact through static, linear and program logic-based evaluation. More sophisticated decision analytic approaches that can account for complexity have long been successfully used in non-health sectors and are now emerging in mental health research and practice. We argue that utilization of advanced decision support tools such as systems modelling and simulation, is now required to bring a necessary discipline to new national and local investments in transforming mental health systems. Conclusion: Systems modelling and simulation delivers an interactive decision analytic tool to test mental health reform and service planning scenarios in a safe environment before implementing them in the real world. The approach drives better decision-making and can inform the scale up of effective and contextually relevant strategies to reduce the burden of mental disorder and enhance the mental wealth of nations

UCT-Kirchberg algebras have nuclear dimension one

We prove that every Kirchberg algebra in the UCT class has nuclear dimension 1. We first show that Kirchberg 2-graph algebras with trivial $K_0$ and finite $K_1$ have nuclear dimension 1 by adapting a technique developed by Winter and Zacharias for Cuntz algebras. We then prove that every Kirchberg algebra in the UCT class is a direct limit of 2-graph algebras to obtain our main theorem.Comment: 21 pages. Version 2: reference [2] has been added, and the discussion in the introduction updated; a small but important typo has been corrected in the definition of the graph E_T. Version 3: Some typo's corrected and references updated; reference [2] corrected as we had accidentally omitted one of the authors' names in the previous version (sorry Aaron!); this version to appear in Adv. Mat

Musculoskeletal Injuries and Outcomes Pre- and Post- Emergency Medicine Training Program

Introduction: Musculoskeletal injuries (MSI) comprise a large portion of the trauma burden in low- and middle-income countries (LMIC). Rwanda recently launched its first emergency medicine training program (EMTP) at the University Teaching Hospital-Kigali (UTH-K), which may help to treat such injuries; yet no current epidemiological data is available on MSI in Rwanda.Methods: We conducted this pre-post study during two data collection periods at the UTH-K from November 2012 to July 2016. Data collection for MSI is limited and thus is specific to fractures. We included all patients with open, closed, or mixed fractures, hereafter referred to as MSI. Gathered information included demographics and outcomes including death, traumatic complications, and length of hospital stay, before and after the implementation of the EMTP.Results: We collected data from 3609 patients. Of those records, 691 patients were treated for fractures, and 674 of them had sufficient EMTP data measured for inclusion in the analysis of results (279 from pre-EMTP and 375 from post-EMTP). Patient demographics demonstrate that a majority of MSI cases are male (71.6% male vs 28.4% female) and young (64.3% below 35 years of age). Among mechanisms of injury, major causes included road traffic accidents (48.1%), falls (34.2%), and assault (6.0%). There was also an observed association between EMTP and trends of the three primary outcomes: a reduction of death in the emergency department (ED) from those with MSI by 89.9%, from 2.51% to 0.25% (p = 0.0077); a reduction in traumatic complications for MSI patients by 71.7%, from 3.58% to 1.01% (p = 0.0211); and a reduction in duration of stay in the ED among those with MSI by 52.7% or 2.81 days on average, from 5.33 to 2.52 days (p = 0.0437).Conclusion: This study reveals the current epidemiology of MSI morbidity and mortality for a major Rwandan teaching hospital and the potential impacts of EM training implementation among those with MSI. Residency training programs such as EMTP appear capable of reducing mortality, complications, and ED length of stay among those with MSI caused by fractures. Such findings underscore the efficacy and importance of investments in educating the next generation of health professionals to combat prevalent MSI within their communities

One-year outcomes after transcatheter insertion of an interatrial shunt device for the management of heart failure with preserved ejection fraction

Background—Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required. Methods and Results—Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II–IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class (P<0.001), quality of life (Minnesota Living with Heart Failure score, P<0.001), and 6-minute walk distance (P<0.01). Echocardiography showed a small, stable reduction in left ventricular end-diastolic volume index (P<0.001), with a concomitant small stable increase in the right ventricular end-diastolic volume index (P<0.001). Invasive hemodynamic studies performed in a subset of patients demonstrated a sustained reduction in the workload corrected exercise pulmonary capillary wedge pressure (P<0.01). Survival at 1 year was 95%, and there was no evidence of device-related complications. Conclusions—These results provide evidence of safety and sustained clinical benefit in heart failure with preserved ejection fraction patients 1 year after interatrial septal shunt device implantation. Randomized, blinded studies are underway to confirm these observations

Initiation of a critical pathway for pancreaticoduodenectomy at an academic institution -- the first step in multi-disciplinary team building

Objective: This study was designed to identify quantifiable parameters to track performance improvements brought about by the implementation of a critical pathway for complex alimentary tract surgery. Background: Pancreaticoduodenectomy (PD) is a complex general surgical procedure performed in varying numbers at many academic institutions. Originally associated with significant perioperative morbidity and mortality, multiple studies have now shown that this operation can be performed quite safely at high volume institutions that develop a particular expertise. Critical pathways are one of the key tools used to achieve consistently excellent outcomes as these institutions. It remains to be determined if implementation of a critical pathway at an academic institution with prior moderate experience with PD will result in performance gains and improved outcomes. Methods: Between January 1, 2004 and October 15, 2006 135 patients underwent PD, 44 before the implementation of a critical pathway on October 15, 2005, and 91 after. Perioperative and postoperative parameters were analyzed retrospectively to identify those that could be used to track performance improvement and outcomes. Key aspects of the pathway include spending the night of surgery in the intensive care unit with careful attention to fluid balance, early mobilization on post-operative day one, aggressive early removal of encumbrances such as nasogastric tubes and urinary catheters, early post-operative feeding, and targeting discharge for postoperative day 6 or 7. Results: The pre- and post-pathway implementation groups were not statistically different with regards to age, sex, race, or pathology (malignant versus benign). Perioperative mortality, operative blood loss, and number of transfused units of packed red blood cells were also similar. As compared to the pre-pathway group, the post-pathway group had a significantly shorter postoperative length of stay (13 versus 7 days, P ≤ 0.0001), operative time (435 ± 14 minutes versus 379 ± 12 minutes, P ≤ 0.0001), and in room non-operative time (95 ± 4 minutes versus 76 ± 2 minutes, P ≤ 0.0001). Total hospital charges were significantly reduced from $240,242 ±$32,490 versus $126,566 ±$4883 (P ≤ 0.0001) after pathway implementation. Postoperative complication rates remained constant (44% pre-pathway versus 37% after, P = NS). Readmission rates were not negatively affected by the reduction in length of stay, with a 7% readmission rate prior to implementation and a 7.7% rate after implementation. Conclusion: Implementation of a critical pathway for a complex procedure can be demonstrated to improve short-term outcomes at an academic institution. This improvement can be quantified and tracked and has implications for better utilization of resources (greater OR and hospital bed availability) and overall cost containment. With a very conservative estimate of 75 pancreaticoduodenectomies per year by this group, this translates to a savings of 450 hospital days and over $8,550,000 in hospital charges on an annual basis. As we enter the pay for performance era, institutions will be required to generate such data in order to retain patient volumes, attract new patients, and receive incentive payments for high quality services rendered