Leveraging global operations innovation to create sustainable competitive advantage

Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Engineering Systems Division; in conjunction with the Leaders for Manufacturing Program at MIT, 2008.Includes bibliographical references (p. 89-91).High fixed costs and the emergence of globalization have forced traditional domestic automotive mass producers to the brink of bankruptcy. This thesis focuses on the global growth strategy of a Tier 1 automotive supplier and examines causal relationships between that strategy and the system stakeholders who execute and support it. The literature review examines current research to illustrate the benefit of approaching globalization with a process-driven, systems-based mindset. Current literature offers insight into improved financial measures that traditional mass producing firms can employ to streamline decision making and shift the mindset of leaders to engage employees, suppliers, and customers around a long-term systems based operating strategy. The thesis is based upon three core experiences the author had at American Axle to illustrate the importance of systems-based operations innovation. The literature review in conjunction with the internship experience is used to illustrate opportunities for American Axle to improve its operating strategy. The paper highlights traditional approaches currently used inside the company and offers solutions to change employee behavior throughout American Axle's global manufacturing system. The thesis examines behaviors, metrics, and results often seen in an absorption cost environment where there are weak operational controls and non-standard corporate scorecards. Using current research and professional industry experience, I will argue robust operational controls and metrics, aligned with an overarching systems approach that considers the long term implications of today's decisions, are essential components to the viable, long term success of any global enterprise.Andrew P. Storm.S.M.M.B.A

There and (slowly) back again: Entropy-driven hysteresis in a model of DNA overstretching

When pulled along its axis, double-stranded DNA elongates abruptly at a force of about 65 pN. Two physical pictures have been developed to describe this overstretched state. The first proposes that strong forces induce a phase transition to a molten state consisting of unhybridized single strands. The second picture instead introduces an elongated hybridized phase, called S-DNA, structurally and thermodynamically distinct from standard B-DNA. Little thermodynamic evidence exists to discriminate directly between these competing pictures. Here we show that within a microscopic model of DNA we can distinguish between the dynamics associated with each. In experiment, considerable hysteresis in a cycle of stretching and shortening develops as temperature is increased. Since there are few possible causes of hysteresis in a system whose extent is appreciable in only one dimension, such behavior offers a discriminating test of the two pictures of overstretching. Most experiments are performed upon nicked DNA, permitting the detachment (`unpeeling') of strands. We show that the long-wavelength progression of the unpeeled front generates hysteresis, the character of which agrees with experiment only if we assume the existence of S-DNA. We also show that internal melting (distinct from unpeeling) can generate hysteresis, the degree of which is strongly dependent upon the nonextensive loop entropy of single-stranded DNA.Comment: 18 pages, 10 figure

Trajectory of long-term outcome in severe pediatric diffuse axonal injury: An exploratory study

Introduction: Pediatric severe traumatic brain injury (TBI) is one of the leading causes of disability and death. One of the classic pathoanatomic brain injury lesions following severe pediatric TBI is diffuse (multifocal) axonal injury (DAI). In this single institution study, our overarching goal was to describe the clinical characteristics and long-term outcome trajectory of severe pediatric TBI patients with DAI.Methods: Pediatric patients (<18 years of age) with severe TBI who had DAI were retrospectively reviewed. We evaluated the effect of age, sex, Glasgow Coma Scale (GCS) score, early fever ≥ 38.5°C during the first day post-injury, the extent of ICP-directed therapy needed with the Pediatric Intensity Level of Therapy (PILOT) score, and MRI within the first week following trauma and analyzed their association with outcome using the Glasgow Outcome Score—Extended (GOS-E) scale at discharge, 6 months, 1, 5, and 10 years following injury.Results: Fifty-six pediatric patients with severe traumatic DAI were analyzed. The majority of the patients were >5 years of age and male. There were 2 mortalities. At discharge, 56% (30/54) of the surviving patients had unfavorable outcome. Sixty five percent (35/54) of surviving children were followed up to 10 years post-injury, and 71% (25/35) of them made a favorable recovery. Early fever and extensive DAI on MRI were associated with worse long-term outcomes.Conclusion: We describe the long-term trajectory outcome of severe pediatric TBI patients with pure DAI. While this was a single institution study with a small sample size, the majority of the children survived. Over one-third of our surviving children were lost to follow-up. Of the surviving children who had follow-up for 10 years after injury, the majority of these children made a favorable recovery

Retrospective Dataset and Survey Analyses Identify Gaps in Data Collection for Craniopharyngioma and Priorities of Patients and Families Affected by the Disease

Introduction: Craniopharyngioma is a rare, low-grade tumor located in the suprasellar region of the brain, near critical structures like the pituitary gland. Here, we concurrently investigate the status of clinical and genomic data in a retrospective craniopharyngioma cohort and survey-based data to better understand patient-relevant outcomes associated with existing therapies and provide a foundation to inform new treatment strategies. Methods: Clinical, genomic, and outcome data for a retrospective cohort of patients with craniopharyngioma were collected and reviewed through the Children\u27s Brain Tumor Network (CBTN) database. An anonymous survey was distributed to patients and families with a diagnosis of craniopharyngioma to understand their experiences throughout diagnosis and treatment. Results: The CBTN repository revealed a large proportion of patients (40 - 70%) with specimens that are available for sequencing but lacked relevant quality of life (QoL) and functional outcomes. Frequencies of reported patient comorbidities ranged from 20 to 25%, which is significantly lower than historically reported. Survey results from 159 patients/families identified differences in treatment considerations at time of diagnosis versus time of recurrence. In retrospective review, patients and families identified preference for therapy that would improve QoL, rather than decrease risk of recurrence (mean 3.9 vs. 4.4 of 5) and identified endocrine issues as having the greatest impact on patients\u27 lives. Conclusions: This work highlights the importance of prospective collection of QoL and functional metrics alongside robust clinical and molecular correlates in individuals with craniopharyngioma. Such comprehensive measures will facilitate biologically relevant therapeutic strategies that also prioritize patient needs

Unsupervised Machine Learning Using K-Means Identifies Radiomic Subgroups of Pediatric Low-Grade Gliomas That Correlate With Key Molecular Markers

Introduction: Despite advancements in molecular and histopathologic characterization of pediatric low-grade gliomas (pLGGs), there remains significant phenotypic heterogeneity among tumors with similar categorizations. We hypothesized that an unsupervised machine learning approach based on radiomic features may reveal distinct pLGG imaging subtypes. Methods: Multi-parametric MR images (T1 pre- and post-contrast, T2, and T2 FLAIR) from 157 patients with pLGGs were collected and 881 quantitative radiomic features were extracted from tumorous region. Clustering was performed using K-means after applying principal component analysis (PCA) for feature dimensionality reduction. Molecular and demographic data was obtained from the PedCBioportal and compared between imaging subtypes. Results: K-means identified three distinct imaging-based subtypes. Subtypes differed in mutational frequencies of BRAF (p \u3c 0.05) as well as the gene expression of BRAF (p\u3c0.05). It was also found that age (p \u3c 0.05), tumor location (p \u3c 0.01), and tumor histology (p \u3c 0.0001) differed significantly between the imaging subtypes. Conclusion: In this exploratory work, it was found that clustering of pLGGs based on radiomic features identifies distinct, imaging-based subtypes that correlate with important molecular markers and demographic details. This finding supports the notion that incorporation of radiomic data could augment our ability to better characterize pLGGs

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition

Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal

The canonical Wnt/β-catenin signaling pathway governs diverse developmental, homeostatic and pathologic processes. Palmitoylated Wnt ligands engage cell surface Frizzled (Fzd) receptors and Lrp5/6 co-receptors enabling β-catenin nuclear translocation and Tcf/Lef-dependent gene transactivation1–3. Mutations in Wnt downstream signaling components have revealed diverse functions presumptively attributed to Wnt ligands themselves, although direct attribution remains elusive, as complicated by redundancy between 19 mammalian Wnts and 10 Fzds1 and Wnt hydrophobicity2,3. For example, individual Wnt ligand mutations have not revealed homeostatic phenotypes in the intestinal epithelium4, an archetypal canonical Wnt pathway-dependent rapidly self-renewing tissue whose regeneration is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs)5–9. R-spondin ligands (Rspo1–4) engage distinct Lgr4-6 and Rnf43/Znrf3 receptor classes10–13, markedly potentiate canonical Wnt/β-catenin signaling and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo8,14–17. However, the interchangeability, functional cooperation and relative contributions of Wnt versus Rspo ligands to in vivo canonical Wnt signaling and ISC biology remain unknown. Here, we deconstructed functional roles of Wnt versus Rspo ligands in the intestinal crypt stem cell niche. We demonstrate that the default fate of Lgr5+ ISCs is lineage commitment, escape from which requires both Rspo and Wnt ligands. However, gain-of-function studies using Rspo versus a novel non-lipidated Wnt analog reveal qualitatively distinct, non-interchangeable roles for these ligands in ISCs. Wnts are insufficient to induce Lgr5+ ISC self-renewal, but rather confer a basal competency by maintaining Rspo receptor expression that enables Rspo to actively drive and specify the extent of stem cell expansion. This functionally non-equivalent yet cooperative interplay between Wnt and Rspo ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precision control of tissue regeneration

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition

Spectacular Nucleosynthesis from Early Massive Stars

Stars that formed with an initial mass of over 50 M ⊙ are very rare today, but they are thought to be more common in the early Universe. The fates of those early, metal-poor, massive stars are highly uncertain. Most are expected to directly collapse to black holes, while some may explode as a result of rotationally powered engines or the pair-creation instability. We present the chemical abundances of J0931+0038, a nearby low-mass star identified in early follow-up of the SDSS-V Milky Way Mapper, which preserves the signature of unusual nucleosynthesis from a massive star in the early Universe. J0931+0038 has a relatively high metallicity ([Fe/H] = −1.76 ± 0.13) but an extreme odd–even abundance pattern, with some of the lowest known abundance ratios of [N/Fe], [Na/Fe], [K/Fe], [Sc/Fe], and [Ba/Fe]. The implication is that a majority of its metals originated in a single extremely metal-poor nucleosynthetic source. An extensive search through nucleosynthesis predictions finds a clear preference for progenitors with initial mass >50 M ⊙, making J0931+0038 one of the first observational constraints on nucleosynthesis in this mass range. However, the full abundance pattern is not matched by any models in the literature. J0931+0038 thus presents a challenge for the next generation of nucleosynthesis models and motivates the study of high-mass progenitor stars impacted by convection, rotation, jets, and/or binary companions. Though rare, more examples of unusual early nucleosynthesis in metal-poor stars should be found in upcoming large spectroscopic surveys