Diseases Commons^™

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

Statins: Masked Anti-Epileptic Warriors, Govinda Khatri, Priya Kotak, Ayush Kumar, Mohammad Mehedi Hasan

Medical College Documents

No abstract provided.

Microplastics In Freshly Fallen Snow: How May It Adversely Impact Human Health And Exacerbate The Covid-19 Crisis?, Ayesha Liaquat, Aleena Kashif, Sushma Rathi, Alishba Raza

Medical College Documents

No abstract provided.

Updated Estimates Of Sepsis Hospitalizations At United States Academic Medical Centers, Hei Kit Chan, Swapnil Khose, Summer Chavez, Bela Patel, Henry E Wang

Faculty, Staff and Student Publications

Objective: Sepsis is a major public health problem. Understanding the epidemiology of sepsis subtypes is important to quantify the magnitude of the problem and identify targets for system wide treatment strategies. We sought to describe the current national epidemiology of community-acquired (CAS), hospital-acquired (HAS) and healthcare-associated sepsis (HCAS) hospitalizations among academic medical centers in the United States using current discharge diagnosis taxonomies.

Methods: Retrospective analysis of patient discharge data from the Vizient Clinical Data Base/Resource Manager. We identified sepsis hospitalizations using four ICD-10 coding strategies: (1) "Martin" sepsis codes (21 ICD-10 codes), (2) "Angus" sepsis codes (ICD-10 infection + ICD-10 …

Barriers To Care For Poststroke Visual Deficits In Alberta, Canada, Kiran Pohar Manhas, Karim F. Damji, Katelyn Brehon, Jennis Jiang, Peter Faris, Fiona Costello

Department of Ophthalmology & Visual Sciences

Poststroke visual impairment (VI) negatively affects rehabilitation potential and quality of life for stroke survivors. In this cross-sectional observational study, stroke survivors and providers were surveyed to quantify perspectives regarding care for poststroke VI in Alberta, Canada (n = 46 survivors; n = 87 providers). Few patients (35%) felt prepared to cope with VI at the time of discharge from acute stroke and inpatient rehabilitation settings. Less than 25% of stroke survivors, and <16% of providers, felt referral processes were adequate. 95.2% of providers and 82% of stroke survivors advocated for a provincial clinical pathway to improve care quality for poststroke VI.

Ribonucleotide Reductase Subunit Switching In Hepatoblastoma Drug Response And Relapse, Anthony Brown

Theses and Dissertations (ETD)

Hepatoblastoma is the most common primary liver cancer in infants and young children. Despite being a very rare cancer that accounts for only 0.5-2% if all childhood cancer cases, HB has the largest increase in incidence among childhood cancers in the United States and worldwide. The five-year survival rate of children with the aggressive forms of HB, including those that have developed metastatic or recurrent diseases, is less than 40% due to the lack of effective treatment. We aim to identify targetable mechanisms underlying the progression and drug resistance of high-risk HB. Our recent work on HB mouse and organoid …

Stromal Vascular Fraction Restores Vasodilatory Function By Reversing Mitochondrial Dysfunction And Oxidative Stress In Aging-Induced Coronary Microvascular Disease., Evan Paul Tracy

Electronic Theses and Dissertations

Background: Coronary Microvascular Disease (CMD) presents in aging post-menopausal women with chronic angina due to microvascular hyperconstriction. The objective was to identify mechanisms of adipose stromal vascular fraction’s (SVF) restorative effects on vasodilation. We hypothesize aging-induced CMD is caused by a) abrogated flow-mediated dilation (FMD) due to loss of nitric oxide signaling and b) ROS-dependent βADR desensitization & internalization, reversible by ameliorating mitochondrial dysfunction and oxidative stress with SVF. Methods: Coronary microvessels were isolated from female rats either young, old, or old with SVF tail-vein injection (OSVF). Pressure myography, RNA-sequencing, immunofluorescence, Western blotting, and morphological analysis were performed to …

Nursing Perspectives And Opinions On Early Or Delayed Sepsis Treatment: A Mixed Methods Approach, Pamela L. Harris

Theses and Dissertations (ETD)

Purpose. Each year at least 1.7 million adults in America develop sepsis. Sepsis can lead to life threatening organ dysfunction, severe hypotension, and death when severe sepsis or septic shock is involved. Sepsis is responsible for 50% of acute kidney injury (AKI), which is the most common form of organ dysfunction seen in critical care. Sepsis associated AKI results in loss of, or decreased renal function, is associated with adverse long-term outcomes, and carries a higher mortality rate than non-septic AKI, sepsis without AKI, or septic shock without AKI. Surviving sepsis guidelines suggests a 1-hour window from the time of …

Inflammatory Response Following Hemorrhagic Stroke: The Role Of Cytokines, Patrick Devlin

Theses and Dissertations (ETD)

Hemorrhagic stroke is a dangerous form of stroke resulting from the rupturing of weakened blood vessels, releasing blood that increases intracranial pressure and causes the death of surrounding tissue. Treatment options are improving but remain limited, as evidenced by this condition being characterized by high rates of mortality as well as long-term morbidity. Unregulated inflammatory responses that occur following injury may be partially to blame for these poor outcomes. In response to any injury, the immune system releases cytokines to recruit immune cell activation and promote inflammation. But after hemorrhagic stroke, whether aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH), …

Combined Laryngeal Cleft Injection Laryngoplasty And Salivary Botulinum Toxin For Saliva Aspiration, Justin Nguyen, Julina Ongkasuwan, Grace Anand, Elton M Lambert

Faculty, Staff and Students Publications

OBJECTIVES: Children with type I laryngeal clefts and sialorrhea can have posterior drooling, aspiration of oral secretions, and respiratory complications. Laryngeal cleft injection laryngoplasty (LCIL) and salivary botulinum injections (Sal-Bot) have been used separately for short-term treatment of type I laryngeal clefts and sialorrhea. Our goal was to evaluate combined LCIL and Sal-Bot and create recommendations for further treatment based on response to initial treatment.

METHODS: Retrospective chart review of nine patients who underwent direct laryngoscopy and bronchoscopy with combined LCIL and Sal-Bot from 2012 to 2019. Charts were reviewed for patient characteristics, response to treatment, and pre and post-op …

Surgical Extraction Of Traumatic Lodgment Of A Pen Nib Between The Eye And Nasal Bridge Of An Infant: A Case Report, Krishna Shah, Vaishali Prajapati, Smeet Desai, Karishma Dhaval Desai, Mayur B Wanjari, Deepika Singhal

Faculty, Staff and Students Publications

Unintentional eye injuries are common in small children. If left unobserved by parents or caretakers, it is challenging to assess as the kids are in distress and pain. Penetrating trauma in or near the eye requires urgent treatment as it can lead to infection and other complications. Early diagnosis and management help avoid further complications. An 11-month-old female was presented by her parents at a tertiary care clinic with inconsolable crying and swelling over the right eye's upper lid for one day. There was a history of possible trauma with a pen while the child was playing. During the examination, …

Unraveling The Effects Of Aerobic Exercise And Erk5 Signaling In The Solid Tumor Microenvironment Using Murine Models, Hannah Savage

Dissertations and Theses (Open Access)

Solid tumors are comprised of multiple cell types which communicate and work together to promote tumor progression. Advances in the treatment of solid tumors have armed clinicians with more efficacious pharmacologic agents and combinations. However, a focus on drug adjuvants in the treatment of solid cancer has left gaps in knowledge regarding non-pharmacologic treatment adjuvants, like aerobic exercise. The current dissertation investigates pharmacologic and non-pharmacologic based approaches to remodel the solid tumor microenvironment landscape and alter therapeutic efficacy. We disassemble compartments of the tumor microenvironment, including tumor vasculature and immune infiltrate, using mouse models and single cell techniques, to elucidate …

Development Of Graphical Models And Statistical Physics Motivated Approaches To Genomic Investigations, Yashwanth Lagisetty

Dissertations and Theses (Open Access)

Identifying genes involved in disease pathology has been a goal of genomic research since the early days of the field. However, as technology improves and the body of research grows, we are faced with more questions than answers. Among these is the pressing matter of our incomplete understanding of the genetic underpinnings of complex diseases. Many hypotheses offer explanations as to why direct and independent analyses of variants, as done in genome-wide association studies (GWAS), may not fully elucidate disease genetics. These range from pointing out flaws in statistical testing to invoking the complex dynamics of epigenetic processes. In the …

Cell-Free Dna Sequencing In Multiple Myeloma, Russell Irwin

Dissertations and Theses (Open Access)

Multiple myeloma (MM) is an incurable plasma cell dyscrasia. Recent advances in MM therapy, including CAR-T therapy, have increased survival and shown the value of assessing treatment response with great sensitivity, both in acute and long-term settings. Cell-free DNA, DNA fragments which are released into circulation as a part of normal cellular turnover, is a useful and dynamic biomarker in cancer patients due to the presence of circulating tumor DNA (ctDNA), which is readily identified using next generation sequencing. Here we report the analytical sensitivity, applicability, consistency, and prognostic ability of M5Seq, a novel hybrid capture panel designed for MM …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Radioluminescence Based Biochemical Sensing And Imaging Strategies To Measure Local Drug Release And Ph, Gretchen B. Schober

All Dissertations

In this dissertation we describe methods for measuring infection relevant biochemical analytes using radioluminescent and ultrasound luminescent materials. Films and nanoparticles fabricated with europium doped gadolinium oxysulfide (Gd₂O₂S:Eu³⁺) are used to quantitatively measure radiolabeled pharmaceutical concentration, specifically tritium labeled vancomycin (³H-vancomycin). Europium and dysprosium doped strontium aluminate is used to fabricate an ultrasound modulated, pH sensing film. These methods are indicated for theranostic evaluation of implant associated infection. Bacterial biofilms are inherently resistant to traditional antibiotic treatment and can coat biomedical implants. These biofilm related infections are difficult or impossible to eradicate …

Histomonosis In Turkeys – Factors Influencing Transmission, Pathogenesis, And The Search For Prophylactic Or Therapeutic Compounds, Thainá Landim De Barros

Graduate Theses and Dissertations

The incidence of histomonosis has been increasing in poultry since the ban of prophylactic and therapeutic compounds. Histomonosis is caused by the protozoa Histomonas meleagridis. The objective of this dissertation was to investigate factors impacting the pathogenesis and transmission of histomonosis and to evaluate compounds that could potentially prevent or reduce the severity of histomonosis in turkeys. In the first study, the effect of sodium chlorate and sodium nitrate on reducing histomonads growth was tested in vitro and added to a basal turkey diet. A decrease in the growth of histomonads in vitro was observed, but no in vivo effect …

Infection And Transmission Determinants Of Flea-Borne Rickettsioses, Hanna J. Laukaitis

Graduate Theses and Dissertations (2019 - present)

The genus Rickettsia is comprised of Gram-negative, obligate intracellular bacteria that are spread by hematophagous arthropods. Elucidating the factors conferring rickettsial virulence has perplexed investigators for decades, complicated by the lack of efficient genetic tools necessary to uncover rickettsial- and vector-specific factors contributing to persistence. The advent of transposon mutagenesis has enabled the field to make vast developments in uncovering novel rickettsial mechanisms utilized in various host backgrounds. Thus, the aim of this study was to generate Rickettsia felis transposon mutants and characterize novel phenotypes associated with genetic disruption in an arthropod background. Distribution of rickettsiae is reliant on the …

Intestinal Microbiota Analysis Of Broiler Chickens Under Necrotic Enteritis Challenge And Tributyrin Supplementation, Taylor Nicole Mckinney

Graduate Theses and Dissertations

Poultry is a staple protein source for most of the planet. Until recently, antibiotic growth promoters (AGPs) were used to prevent illnesses in commercial chicken production. Currently, this is not possible due to regulations and consumer concern, but without such a preventative, diseases like necrotic enteritis (NE) have reemerged, posing a threat to bird health, and ultimately, our food source. Necrotic enteritis is a severe gastrointestinal disease caused by the gram-positive pathogen, Clostridium perfringens. Clinical features of this disease are diarrhea, intestinal lesions, and death, with a high transmission rate. In a subclinical form, growth performance is diminished and is …

An Analysis Of Demographics And Risk Factors Associated With Increasing Syphilis Cases In Iowa, Eleanore H. Nelson

Capstone Experience: Master of Public Health

Background:

Syphilis is easily detectable and treatable with the appropriate medical attention, yet national incidence rates have been on the rise since reaching an all-time low in 2000 (Shockman et al, 2014). Similar to HIV, men who have sex with other men (MSM), represent most syphilis transmission, yet in recent years, syphilis rates have concerningly increased among both genders and among all racial/ethnic groups (CDC, 2019).

Methods:

Surveillance data was collected on all syphilis cases reported to the Iowa Department of Public Health (IDPH) regarding demographics and risk factors of cases. Variables were analyzed using chi-square and Fisher’s exact tests, …

Glutathione Peroxidase 2 Is A Metabolic Driver Of The Tumor Immune Microenvironment And Immune Checkpoint Inhibitor Response, Kazi Mokim Ahmed, Ratna Veeramachaneni, Defeng Deng, Nagireddy Putluri, Vasanta Putluri, Maria F Cardenas, David A Wheeler, William K Decker, Andy I Frederick, Sawad Kazi, Andrew G Sikora, Vlad C Sandulache, Mitchell J Frederick

Faculty, Staff and Students Publications

BACKGROUND: The existence of immunologically 'cold tumors' frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden.

METHODS: Using a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot …

3’Utr Shortening Of Has2 Promotes Hyaluronan Hyper-Synthesis And Bioenergetic Dysfunction In Pulmonary Hypertension, Victor Tseng, Scott D Collum, Ayed Allawzi, Kathryn Crotty, Samantha Yeligar, Aaron Trammell, M Ryan Smith, Bum-Yong Kang, Roy L Sutliff, Jennifer L Ingram, Soma S S K Jyothula, Rajarajan A Thandavarayan, Howard J Huang, Eva S Nozik, Eric J Wagner, C Michael Hart, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Pulmonary hypertension (PH) comprises a diverse group of disorders that share a common pathway of pulmonary vascular remodeling leading to right ventricular failure. Development of anti-remodeling strategies is an emerging frontier in PH therapeutics that requires a greater understanding of the interactions between vascular wall cells and their extracellular matrices. The ubiquitous matrix glycan, hyaluronan (HA), is markedly elevated in lungs from patients and experimental models with PH. Herein, we identified HA synthase-2 (HAS2) in the pulmonary artery smooth muscle cell (PASMC) layer as a predominant locus of HA dysregulation. HA upregulation involves depletion of NUDT21, a master regulator of …

Rationale And Design Of Savi-Aos: A Physiologic Study Of Patients With Symptomatic Moderate Aortic Valve Stenosis And Preserved Left Ventricular Ejection Fraction, Rob Eerdekens, Pim Tonino, Jo Zelis, Rik Adrichem, Jung-Min Ahn, Jesse Demandt, Ashkan Eftekhari, Mohamed El Farissi, Phillip Freeman, Abdul Rahman Ihdayhid, Nikolaos Kakouros, Dae-Hee Kim, Seung-Ah Lee, Nicolas M Van Mieghem, Waqas Qureshi, Nils P Johnson

Faculty, Staff and Student Publications

Background: Moderate aortic valve stenosis occurs twice as often as severe aortic stenosis (AS) and carries a similarly poor prognosis. Current European and American guidelines offer limited insight into moderate AS (MAS) patients with unexplained symptoms. Measuring valve physiology at rest while most patients experience symptoms during exertion might represent a conceptual limitation in the current grading of AS severity. The stress aortic valve index (SAVI) may delineate hemodynamically significant AS among patients with MAS.

Objectives: To investigate the diagnostic value of SAVI in symptomatic MAS patients with normal left ventricular ejection fraction (LVEF ≥ 50%): aortic valve area (AVA) …

Placental Pathology In Spontaneous And Iatrogenic Preterm Birth: Different Entities With Unique Pathologic Features, Lucy T Brink, Drucilla J Roberts, Colleen A Wright, Daan G Nel, Pawel T Schubert, Theonia K Boyd, David R Hall, Hein Odendaal

Faculty, Staff and Student Publications

INTRODUCTION: Placental pathology is an important contributor to the understanding of preterm birth and reveals major differences between spontaneous preterm birth (SPTB) and iatrogenic preterm birth (IPTB). The aim of this study was to investigate these relationships.

METHODS: Research midwives collected placentas from 1101 women with singleton pregnancies who were enrolled in the Safe Passage Study. Trained pathology technologists prepared and processed placenta specimens for macroscopic and microscopic examination by designated pathologists. Statistical analyses were done with STATISTICA version 13.

RESULTS: In SPTB we found more cases of accelerated villous maturation; however, the other features of maternal vascular malperfusion (MVM) …

International Prevalence And Mechanisms Of Sars-Cov-2 In Childhood Arterial Ischemic Stroke During The Covid-19 Pandemic, Lauren A Beslow, Shannon C Agner, Jonathan D Santoro, Dipak Ram, Jenny L Wilson, Dana Harrar, Brian Appavu, Stuart M Fraser, Thomas Rossor, Marcela D Torres, Manoëlle Kossorotoff, Yenny C Zuñiga Zambrano, Marta Hernández-Chávez, Sahar M A Hassanein, Dimitrios Zafeiriou, Michael M Dowling, Ilona Kopyta, Nicholas V Stence, Timothy J Bernard, Nomazulu Dlamini

Faculty, Staff and Student Publications

BACKGROUND: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2.

METHODS: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients <18 >years, numbers of incident AIS cases among children (29 days to <18 >years), frequency …

Advances In Head And Neck Cancer Pain, Y Ye, D D Jensen, C T Viet, H L Pan, W M Campana, M Amit, M D Boada

Faculty, Staff and Student Publications

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune …

Anesthesia For Echocardiography And Magnetic Resonance Imaging In The African Clawed Frog (Xenopus Laevis), Antonio F Corno, Noelia E Flores, Wen Li, Thomas H Gomez, Jorge D Salazar

Faculty, Staff and Student Publications

This report describes an anesthesia technique that we used to study cardiovascular anatomy and physiology with echocardiography and cardiac magnetic resonance (CMR) in 46 African clawed frogs (Xenopus laevis) (n = 24 for electrocardiography and n = 22 for CMR). For administration of anesthesia, 3 holding tanks, one each for transportation, sedation, and recovery, were filled with filtered water, with 0.05% buffered tricaine methasulfonate solution (MS-222) added into the sedation tank. Fifteen minutes after the frog was placed in the sedation tank, a paper towel was soaked in MS-222 solution, and the frog was placed in a …

Supporting Self-Management For Patients With Interstitial Lung Diseases: Utility And Acceptability Of Digital Devices, Shima Aran, Orest O Kayder, Teena Chopra, Hani Abujudeh

Faculty, Staff and Student Publications

On December 2020, the US Food and Drug Administration issued the first emergency use authorization for a vaccine for the prevention of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report development of superficial thrombophlebitis in the ipsilateral breast of a 43-year-old female 7 days after receiving the first dose of the Pfizer-BioNTech COVID-19 vaccine. Given that this is the first case of superficial thrombophlebitis in the breast shortly after mRNA vaccination for COVID-19 reported to our knowledge, we suggest that this may be a rare vaccine-related event.

Changes Of Brain Function In Patients With Type 2 Diabetes Mellitus Measured By Different Analysis Methods: A New Coordinate-Based Meta-Analysis Of Neuroimaging, Ze-Yang Li, Teng Ma, Ying Yu, Bo Hu, Yu Han, Hao Xie, Min-Hua Ni, Zhu-Hong Chen, Yang-Ming Zhang, Yu-Xiang Huang, Wen-Hua Li, Wen Wang, Lin-Feng Yan, Guang-Bin Cui

Faculty, Staff and Student Publications

OBJECTIVE: Neuroimaging meta-analysis identified abnormal neural activity alterations in patients with type 2 diabetes mellitus (T2DM), but there was no consistency or heterogeneity analysis between different brain imaging processing strategies. The aim of this meta-analysis was to determine consistent changes of regional brain functions in T2DM

METHODS: Since the indicators obtained using varied post-processing methods reflect different neurophysiological and pathological characteristics, we further conducted a coordinate-based meta-analysis (CBMA) of the two categories of neuroimaging literature, which were grouped according to similar data processing methods: one group included regional homogeneity (ReHo), independent component analysis (ICA), and degree centrality (DC) studies, while …

Geriatric Cardiology: Coming Of Age, Parag Goyal, Min Ji Kwak, Christina Al Malouf, Manish Kumar, Namit Rohant, Abdulla A Damluji, Quin E Denfeld, Kim K Bircher, Ashok Krishnaswami, Karen P Alexander, Daniel E Forman, Michael W Rich, Nanette K Wenger, James N Kirkpatrick, Jerome L Fleg

Faculty, Staff and Student Publications

Older adults with cardiovascular disease (CVD) contend with deficits across multiple domains of health due to age-related physiological changes and the impact of CVD. Multimorbidity, polypharmacy, cognitive changes, and diminished functional capacity, along with changes in the social environment, result in complexity that makes provision of CVD care to older adults challenging. In this review, we first describe the history of geriatric cardiology, an orientation that acknowledges the unique needs of older adults with CVD. Then, we introduce 5 essential principles for meeting the needs of older adults with CVD: 1) recognize and consider the potential impact of multicomplexity; 2) …