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This dissertation describes the development of methodologies that engage strained cyclic intermediates in complexity-generating reactions. One major effort involves the transition metal-catalyzed interception of strained cyclic allenes, which has been accomplished using asymmetric nickel catalysis and palladium catalysis. Additionally, the study of alternative minimally explored strained intermediates including cyclic 1,2,3-trienes and 2,3-heterocyclic allenes are reported. These studies expand on fundamental understanding of structure and reactivity of strained compounds and give rise to diverse libraries of polycyclic products. Studies relating to the in situ generation of various strained cyclic intermediates are also reported. Specifically, these include experimental evaluation of the safety associated with the use of silyl triflates as benzyne precursors as well as the synthesis and evaluation of silyl tosylates as precursors to strained alkynes and allenes.Chapters one and two are related to the development of metal-catalyzed reactions of strained cyclic allenes. Chapter one describes the first catalytic asymmetric reaction involving a strained cyclic allene, which was achieved through the use of nickel catalysis. The scope of the asymmetric annulation reaction is reported, and computational studies performed in collaboration with the Houk Laboratory elucidate the origin of asymmetric induction in the transformation. Chapter two describes the development of a modular annulation reaction of strained allenes enabled by a palladium catalyst. This methodology employs aryl halides and cyclic allene precursors to generate fused heterocyclic products via the formation of two new bonds and a sp3 center. The development of these metal-catalyzed reactions demonstrates that despite their high reactivity and short lifetimes, strained cyclic intermediates can be efficiently engaged in catalysis, to access complex products, often with absolute stereocontrol.Chapter three describes the development of strained 1,2,3-cyclohexatrienes, which have remained underexplored historically, as synthetic building blocks. Studies of the reactivity of the unsubstituted 1,2,3-cyclohexatriene, as well as its mono- and disubstituted derivatives are reported, drastically expanding the scope of reactions known for such intermediates. Combined computational and experimental studies elucidate the factors controlling regioselectivity in reactions of an unsymmetrical strained triene. Furthermore, the potential utility of strained trienes in rapidly generating complex scaffolds is demonstrated through the integration of triene trapping reactions into multistep synthetic sequences to access sp3-rich polycyclic products. These studies highlight the potential of these traditionally avoided species in synthetic chemistry.Chapter four details the study of unsymmetrical strained heterocyclic allenes, particularly 2,3-azacyclohexadienes. Computational studies of the structure of such species, as well as the development of a synthetic route to access precursors to the same, are reported. Scope studies demonstrate the utility of 2,3-azacyclic allenes for accessing complex nitrogen-containing heterocycles, and trends in the regio- and diastereoselectivity observed therein are explored through control experiments. The extension of this study to 2,3-oxacyclic allenes enables their generation under mild conditions for the first time, as well as the first demonstration of their reactivity in dipolar cycloadditions and transition metal-catalyzed reactions. Collectively, this study demonstrates the potential value of unsymmetrical aza- and oxacyclic allenes in heterocycle synthesis.Chapter five describes an evaluation of the safety profile associated with benzyne generation from a silyl triflate precursor which was performed in collaboration with the process development group at Boehringer Ingelheim. Calorimetric analysis supports the safe nature of generating high energy aryne intermediates from silyl triflates under fluoride-mediated conditions.Chapter six illustrates the development of an alternative precursor toward strained cyclic allenes and alkynes. Our studies of strained cyclic allenes revealed that, in some cases, silyl triflate precursors were inaccessible. This study shows that silyl tosylates can serve as alternative precursors to strained cyclic allenes and alkynes.

Background According to the Elaboration Likelihood Model, persuasion can occur via two different routes (the central route and peripheral route), with the route utilized dependent on factors associated with motivation and ability. This study aimed to explore the moderating role of need for cognition (NFC) and perceived relevance on the processing of physical activity messages designed to persuade via either the central route or the peripheral route. Method Participants (N = 50) were randomized to receive messages optimized for central route processing or messages optimized for peripheral route processing. Eye-tracking devices were used to assess attention, which was the primary outcome. Message perceptions and the extent of persuasion (changes in physical activity determinants) were also assessed via self-report as secondary outcomes. Moderator effects were examined using interaction terms within mixed effects models and linear regression models. Results There were no detected interactions between condition and NFC for any of the study outcomes (all ps > .05). Main effects of personal relevance were observed for some self-report outcomes, with increased relevance associated with better processing outcomes. An interaction between need for cognition and personal relevance was observed for perceived behavioral control (p = 0.002); greater relevance was associated with greater perceived behavioral control for those with a higher need for cognition. Conclusion Matching physical activity messages based on NFC may not increase intervention efficacy. Relevance of materials is associated with greater change in physical activity determinants and may be more so among those with a higher NFC.

Let [Formula: see text] be a positive integer and let [Formula: see text] be the set of positive integers less than [Formula: see text] that are relatively prime to [Formula: see text]. If [Formula: see text] can be partitioned into two subsets of equal sum, then [Formula: see text] is called a super totient number. In this paper, we generalize this concept by considering when [Formula: see text] can be partitioned into [Formula: see text] subsets of equal sum. Integers that admit such a partition are called [Formula: see text]-fold super totient numbers. In this paper, we prove that for every odd positive integer [Formula: see text], there exists an integer [Formula: see text] such that for all [Formula: see text], [Formula: see text] is a [Formula: see text]-fold super totient numbers provided that some trivial necessary condition is satisfied. Furthermore, we determine the smallest allowable values for [Formula: see text] and [Formula: see text].

Few guidelines have focused on the care delivered after return of spontaneous circulation (ROSC). Post ROSC best practice guidelines lack clarity about important tasks to accomplish in the first hours after ROSC.We conducted a retrospective cohort analysis of adults who had suffered an in hospital cardiac arrest (IHCA) with ROSC over a two-year period to determine the completion rate of critical tasks in the immediate post-ROSC period: ECG within one hour, ABG within one hour, physician documentation within six hours, and surrogate communication within six hours.In the 113 reviewed cases, there was significant variance between completion of all four (19.4%), three (35.3%), two (32.7%), one (20.6%) and none (1.7%) of these critical post ROSC tasks. We observed that 62.8% of IHCA with ROSC had an ECG obtained within one hour of ROSC. The rate of obtaining an ABG within one hour of ROSC was 76.9%. 49.5% of cases had physician documentation of the resuscitation within six hours of ROSC. The rate of documenting surrogate communication within six hours of ROSC was 69.9%.Our study demonstrated that the completion rates of critical tasks in the post ROSC setting were suboptimal within our patient cohort. This provides a baseline for the development of future best practice guidelines and clinical decision-making aids for post ROSC care after IHCA. This can lead to future research in coupling specific care tasks to post ROSC patient outcomes.

Objective: Time-restricted eating (TRE) restores circadian rhythms in mice, but the evidence to support this in humans is limited. The objective of this study was to investigate the effects of TRE on 24-hour profiles of plasma metabolites, glucoregulatory hormones, and the subcutaneous adipose tissue (SAT) transcriptome in humans. Methods: Men (n = 15, age = 63 [4] years, BMI 30.5 [2.4] kg/m2) were recruited. A 35-hour metabolic ward stay was conducted at baseline and after 8 weeks of 10-hour TRE. Assessment included 24-hour profiles of plasma glucose, nonesterified fatty acid (NEFA), triglyceride, glucoregulatory hormones, and the SAT transcriptome. Dim light melatonin onset and cortisol area under the curve were calculated. Results: TRE did not alter dim light melatonin onset but reduced morning cortisol area under the curve. TRE altered 24-hour profiles of insulin, NEFA, triglyceride, and glucose-dependent insulinotropic peptide and increased transcripts of circadian locomotor output cycles protein kaput (CLOCK) and nuclear receptor subfamily 1 group D member 2 (NR1D2) and decreased period circadian regulator 1 (PER1) and nuclear receptor subfamily 1 group D member 1 (NR1D1) at 12:00 am. The rhythmicity of 450 genes was altered by TRE, which enriched in transcripts for transcription corepressor activity, DNA-binding transcription factor binding, regulation of chromatin organization, and small GTPase binding pathways. Weighted gene coexpression network analysis revealed eigengenes that were correlated with BMI, insulin, and NEFA. Conclusions: TRE restored 24-hour profiles in hormones, metabolites, and genes controlling transcriptional regulation in SAT, which could underpin its metabolic health benefit. Refereed/Peer-reviewed

Supplementary Figure S1.

Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine.Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab ± cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival.Results: A total of 29 SNPs were detected in the case–cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14+1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14+1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14+1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) = 0.57 (0.35–0.95)].Conclusions: DPYD IVS14+1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine. Clin Cancer Res; 17(10); 3455–68. ©2011 AACR.

Alternative credentials, such as micro credentials and digital badges, are increasingly being developed in universities. Primarily aimed at employability, these credentials are being scrutinised as it is argued that they are surrounded by ‘great uncertainty’. We contribute to this scrutiny by examining the forms of subjectivity that result from micro-credentials. We argue that, in their current form, they tend to result in a neoliberal subject. Presented is a counter-narrative that examines the current state of micro-credentials and offers an alternative form that refuses instrumentalist logics. In doing so, we draw from Foucault and postdigital research. The result is a recommendation to implement three principles in the design of micro-credentials. The first is the principle of being embedded in the curriculum, the second is alignment with the university mission, and the third is a critical and reflective pedagogy. This recommendation offers further possible subjectivities.

Sepsis is a major cause of mortality among hospitalized patients worldwide. Shorter time to administration of broad‐spectrum antibiotics is associated with improved outcomes, but early recognition of sepsis remains a major challenge. In a two‐center cohort study with prospective sample collection from 1400 adult patients in emergency departments suspected of sepsis, we sought to determine the diagnostic and prognostic capabilities of a machine‐learning algorithm based on clinical data and a set of uncommonly measured biomarkers. Specifically, we demonstrate that a machine‐learning model developed using this dataset outputs a score with not only diagnostic capability but also prognostic power with respect to hospital length of stay (LOS), 30‐day mortality, and 3‐day inpatient re‐admission both in our entire testing cohort and various subpopulations. The area under the receiver operating curve (AUROC) for diagnosis of sepsis was 0.83. Predicted risk scores for patients with septic shock were higher compared with patients with sepsis but without shock (p

According to the Elaboration Likelihood Model, persuasion can occur via two different routes (the central route and peripheral route), with the route utilized dependent on factors associated with motivation and ability. This study aimed to explore the moderating role of need for cognition (NFC) and perceived relevance on the processing of physical activity messages designed to persuade via either the central route or the peripheral route.Participants (N = 50) were randomized to receive messages optimized for central route processing or messages optimized for peripheral route processing. Eye-tracking devices were used to assess attention, which was the primary outcome. Message perceptions and the extent of persuasion (changes in physical activity determinants) were also assessed via self-report as secondary outcomes. Moderator effects were examined using interaction terms within mixed effects models and linear regression models.There were no detected interactions between condition and NFC for any of the study outcomes (all ps .05). Main effects of personal relevance were observed for some self-report outcomes, with increased relevance associated with better processing outcomes. An interaction between need for cognition and personal relevance was observed for perceived behavioral control (p = 0.002); greater relevance was associated with greater perceived behavioral control for those with a higher need for cognition.Matching physical activity messages based on NFC may not increase intervention efficacy. Relevance of materials is associated with greater change in physical activity determinants and may be more so among those with a higher NFC.

This is not a book to review with any rapid brush strokes. In fact, it is the subtlety of the arguments which repay closer attention. The book is noticeably the product of a number of years of thou...

The essay explores an oblique perspective on language via the field of comparative political theory* (*hereafter CPT). The essay sketches briefly some of the conceptual architecture and genealogy of the comparative political theory enterprise and investigates more specifically the uses of the concepts of culture and language within the core arguments. The discussion distinguishes three rough categories of CPT and correlates these with understandings of language. The discussion then turns to certain problematic aspects of CPT concerned with the concepts of political theory, comparison within political studies and the concept of culture itself. The essay concludes on a critical and circumspect note on the status of CPT within contemporary understandings of political theory.

How the Tibetan Plateau was constructed and evolved in response to ongoing India-Asia convergence since 65-55 Ma is fundamental in understanding processes of continental tectonics. Furthermore, the kinematics and mechanisms of plateau formation and continental deformation have implications for the complex interactions between tectonics, erosion, and climate change in Earth’s most recent history. To provide insights into these processes, my research is focused on the development of the northern margin of the Tibetan Plateau, which is defined by the 350-km-wide and 1300-km-long Cenozoic Qilian Shan-Nan Shan thrust belt. This active fold and thrust system overprinted a region that has a complex pre-Cenozoic tectonic history involving multiple phases of Proterozoic basement deformation and early Paleozoic orogeny. In this work, I integrate geologic mapping, balanced cross section construction and restoration, seismic reflection interpretation, geochronology, thermobarometry, geodetic data analysis, and analogue modeling to investigate the tectonic development of northern Tibet over a range of timescales, from the Proterozoic evolution of central Asian cratons to the active deformation that is shaping the northern margin of the Tibetan Plateau. The magnitude, style, and distribution of Cenozoic shortening strain across northern Tibet can be used to test competing models of continental deformation. The shortening distribution across the Qilian Shan-Nan Shan thrust belt, derived from surface mapping and subsurface seismic reflection profiles, suggests that the modern thickness and elevation of the northern plateau has developed as a result of southward continental underthrusting of Asia beneath Tibet and distributed crustal thickening. The thrust systems in northern Tibet link to the east with > ~1000-km-long parallel left-slip strike-slip faults (i.e., the Haiyuan, Qinling, and Kunlun faults). The along-strike variation of fault offsets and pervasive off-fault deformation along these strike-slip faults create a strain pattern that departs from the expectations of the classic plate-like rigid-body motion and flow-like distributed deformation models of continental deformation. Instead, I propose that the major strike-slip faults formed as a non-rigid bookshelf-fault system where clockwise rotation of northern Tibet drives left-slip bookshelf faulting and related off-strike-slip fault deformation. In addition, I employ a stress-shadow model that uses the characteristic spacing of strike-slip faults and seismogenic-zone thickness estimates across northern Tibet and central Asia to estimate fault strength and the regional stress state. The strike-slip faults in Asia have a low coefficient of fault friction (~0.15), which may explain why deformation penetrates more than 3500 km into Asia from the Himalayan collisional front, and why the interior of Asia is prone to large (M > 7.0) devastating earthquakes along major strike-slip faults.A well-constrained understanding of Cenozoic deformation across northern Tibet allows for better reconstructions of the Proterozoic and Paleozoic tectonics. Field relationships and geochronologic studies reveal that the early Paleozoic Qilian suture, which bounds the southern margin of the North China craton, records the Ordovician-early Silurian closure of the Qilian Ocean via south-dipping subduction beneath the Qaidam continent. The evolution of this ocean and North China’s southern margin has implications for reconstructions of Neoproterozoic and Paleozoic Earth, including the development of the Tethyan and Paleo-Asian Oceanic Domains. By restoring the Phanerozoic deformation along the northern and southern margins of the Tarim and North China cratons, I propose and test a hypothesis that these cratons once stretched westward across present-day Asia, possibly as far west as Baltica, as a continuous Neoproterozoic continent.