Biomechanical determinants of emphysema progression in chronic obstructive pulmonary disease

Emphysema is a disease of the lung parenchyma associated with chronic obstructive pulmonary disease (COPD) and characterized by progressive, irreversible tissue destruction. While chronic inflammation due to repeated noxious particle exposure is the most common environmental risk factor, biomechanical stresses are also known to contribute. It is thought that inflammation-related enzymatic weakening predisposes tissue to mechanical failure, leading to self-propagating parenchymal destruction. However, essential questions regarding the underlying disease mechanisms and their link to overall lung decline remain unanswered. The overarching goals of this dissertation were to relate changes at the cell and tissue level to lung structure and function, and to determine how clinical interventions impact the mechanical balance of parenchymal tissue stresses. First, we use a computational network model of lung volume reduction, a palliative treatment for end-stage emphysema, to demonstrate how recent bronchoscopic, biomaterial-based treatments can achieve similar outcomes as traditional surgical procedures. Next, in a cohort of COPD patients with follow-up computed tomography (CT) imaging, we identify a previously unrecognized structural feature of emphysema that suggests a fundamentally new mechanism of disease progression and potential target for tissue engineering solutions. Finally, we describe the design and implementation of an ex vivo platform for cyclic stretching of precision-cut lung slices, demonstrating a stretch-dependent inflammatory response to acute cigarette smoke extract exposure. In summary, this work combines computational modeling, clinical imaging, and ex vivo measurements to characterize the biomechanical stresses driving emphysema progression and provide new insight that may inform more rational, patient-specific treatment strategies.2020-07-02T00:00:00

Development of X-TOOLSS: Preliminary Design of Space Systems Using Evolutionary Computation

Evolutionary computational (EC) techniques such as genetic algorithms (GA) have been identified as promising methods to explore the design space of mechanical and electrical systems at the earliest stages of design. In this paper the authors summarize their research in the use of evolutionary computation to develop preliminary designs for various space systems. An evolutionary computational solver developed over the course of the research, X-TOOLSS (Exploration Toolset for the Optimization of Launch and Space Systems) is discussed. With the success of early, low-fidelity example problems, an outline of work involving more computationally complex models is discussed

Triceps surae muscle-tendon properties as determinants of the metabolic cost in trained long-distance runners

Purpose: This study aimed to determine whether triceps surae’s muscle architecture and Achilles tendon parameters are related to running metabolic cost (C) in trained long-distance runners. Methods: Seventeen trained male recreational long-distance runners (mean age = 34 years) participated in this study. C was measured during submaximal steady-state running (5 min) at 12 and 16 km h–1 on a treadmill. Ultrasound was used to determine the gastrocnemius medialis (GM), gastrocnemius lateralis (GL), and soleus (SO) muscle architecture, including fascicle length (FL) and pennation angle (PA), and the Achilles tendon cross-sectional area (CSA), resting length and elongation as a function of plantar flexion torque during maximal voluntary plantar flexion. Achilles tendon mechanical (force, elongation, and stiffness) and material (stress, strain, and Young’s modulus) properties were determined. Stepwise multiple linear regressions were used to determine the relationship between independent variables (tendon resting length, CSA, force, elongation, stiffness, stress, strain, Young’s modulus, and FL and PA of triceps surae muscles) and C (J kg–1m–1) at 12 and 16 km h–1. Results: SO PA and Achilles tendon CSA were negatively associated with C (r2 = 0.69; p < 0.001) at 12 km h–1, whereas SO PA was negatively and Achilles tendon stress was positively associated with C (r2 = 0.63; p = 0.001) at 16 km h–1, respectively. Our results presented a small power, and the multiple linear regression’s cause-effect relation was limited due to the low sample size. Conclusion: For a given muscle length, greater SO PA, probably related to short muscle fibers and to a large physiological cross-sectional area, may be beneficial to C. Larger Achilles tendon CSA may determine a better force distribution per tendon area, thereby reducing tendon stress and C at submaximal speeds (12 and 16 km h–1). Furthermore, Achilles tendon morphological and mechanical properties (CSA, stress, and Young’s modulus) and triceps surae muscle architecture (GM PA, GM FL, SO PA, and SO FL) presented large correlations with C

Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVE: Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS: We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS: We replicated the association of variants in the metformin transporter gene $SLC47A1$ with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene $STK11$, the AMPK subunit genes $PRKAA1$ and $PRKAA2$, and a missense SNP in $SLC22A1$, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene $PRKAG2$ (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10$^{−4}$). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest $P$ values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS: We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples

Russell's viper envenomation induces rectus sheath haematoma

Snakebite envenomation causes systemic and local manifestations, which result from the individual or synergistic actions of multiple venom components. The pathological hallmarks of medically important venomous snakes such as the Indian Russell's viper (Daboia russelii) are well known. Envenomation by Russell’s viper is typically characterised by coagulopathies, muscular damage, nephrotoxicity, and neurotoxicity. However, recent reports have revealed several unusual complications that provide a better understanding of Russell’s viper envenomation effects. To further strengthen this, here, we report a case of Russell's viper bite that induced acute abdominal pain, which was intensified on day two and conservatively treated under medical supervision. Both Fothergill and Carnett signs were positive for this patient. An ultrasound imaging revealed a dissimilar dense mass, and the abdominal computed tomography scan confirmed rectus sheath haematoma. The clinical management involved the administration of polyvalent antivenom, packed red blood cells, fresh frozen plasma, and platelets. The patient recovered gradually and was discharged from the hospital eight days after the bite. Overall, this case presentation shares an uncommon experience and adds new insights into the complex series of rare pathological events associated with Russell's viper bites in India. The scientific documentation of relatively infrequent entities based on an ongoing living assessment of medical experiences, for example, this rectus sheath haematoma, constitutes valuable guidance for an adequate diagnosis and timely treatment. Essential awareness among clinicians and further research on understanding the molecular relationship between Russell’s viper venom and rectus sheath haematoma will improve patient outcomes and understanding of this condition, respectively