Investigative Techniques Commons^™

Molecular Architecture Of Chitin And Chitosan-Dominated Cell Walls In Zygomycetous Fungal Pathogens By Solid-State Nmr, Qinghui Cheng, Malitha C. Dickwella Widanage, Jayasubba Reddy Yarava, Ankur Ankur, Jean Paul Latgé, Ping Wang, Tuo Wang

School of Medicine Faculty Publications

Zygomycetous fungal infections pose an emerging medical threat among individuals with compromised immunity and metabolic abnormalities. Our pathophysiological understanding of these infections, particularly the role of fungal cell walls in growth and immune response, remains limited. Here we conducted multidimensional solid-state NMR analysis to examine cell walls in five Mucorales species, including key mucormycosis causative agents like Rhizopus and Mucor species. We show that the rigid core of the cell wall primarily comprises highly polymorphic chitin and chitosan, with minimal quantities of β-glucans linked to a specific chitin subtype. Chitosan emerges as a pivotal molecule preserving hydration and dynamics. Some …

Cd8Α Structural Domains Enhance Gucy2c Car-T Cell Efficacy, Trevor R. Baybutt, Ariana A. Entezari, Adi Caspi, Ross E. Staudt, Robert D. Carlson, Scott A. Waldman, Adam E. Snook

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural …

Removal Of Common Antimicrobial Agents By Sustained Low- Efficiency Dialysis, Joanna Q. Hudson Pharmd, Bcps, Fasn, Fccp, Madelyn N. Hilgers Bs, Pharmd Candidate, Elvira O. Gosmanova Md

Faculty Publications

Adequate dosing of antimicrobials is paramount for treating infections in critically ill patients undergoing kidney replacement therapy; however, little is known about antimicrobial removal by sustained low-efficiency dialysis (SLED). The objective was to quantify the removal of cefepime, daptomycin, meropenem, piperacillin–tazobactam, and vancomycin in patients undergoing SLED. Adult patients ≥18 years with acute kidney injury (AKI) or end-stage kidney disease receiving one of the select antimicrobials and requiring SLED were included. Blood and dialysate flow rates were maintained at 250 and 100 mL/min, respectively. Simultaneous arterial and venous blood samples for the analysis of antibiotic concentrations were collected hourly for …

Immunoactive Signatures Of Circulating Trna- And Rrna-Derived Rnas In Chronic Obstructive Pulmonary Disease, Megumi Shigematsu, Takuya Kawamura, Deepak Deshpande, Yohei Kirino

Computational Medicine Center Faculty Papers

Chronic obstructive pulmonary disease (COPD) is the most prevalent lung disease, and macrophages play a central role in the inflammatory response in COPD. We here report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma from patients with COPD. While circulating sncRNAs are increasingly recognized for their regulatory roles and biomarker potential in various diseases, the conventional RNA sequencing (RNA-seq) method cannot fully capture these circulating sncRNAs due to their heterogeneous terminal structures. By pre-treating the plasma RNAs with T4 polynucleotide kinase, which converts all RNAs to those with RNA-seq susceptible ends (5′-phosphate and 3′-hydroxyl), we comprehensively sequenced …

Roles Of Hydrogen Sulfide (H2s) As A Potential Therapeutic Agent In Cardiovascular Diseases: A Narrative Review, Kazi N. Islam, Ivan D. Nguyen, Rahib Islam, Humza Pirzadah, Hassan Malik

School of Medicine Faculty Publications

Cardiovascular disease (CVD) stands as one of the leading causes of morbidity and mortality worldwide, and the continued search for novel therapeutics is vital for addressing this global health challenge. Over the past decade, hydrogen sulfide (H₂S) has garnered significant attention in the field of medical research, as it has been proven to be a cardioprotective gaseous signaling molecule. It joins nitric oxide and carbon monoxide as endogenously produced gasotransmitters. As for its mechanism, H₂S functions through the posttranslational addition of a sulfur group to cysteine residues on target proteins in a process called sulfhydration. As a result, the observed …

Association Of High Fibrinogen To Albumin Ratio With Long-Term Mortality In Patients With Spontaneous Intracerebral Hemorrhage, Shiping Chen, Yu Zhang, Yangchun Xiao, Xin Cheng, Liyuan Peng, Yixin Tian, Tiangui Li, Jialing He, Pengfei Hao, Weelic Chong, Yang Hai, Chao You, Fang Fang

Department of Medical Oncology Faculty Papers

BACKGROUND: The association between fibrinogen-to-albumin ratio (FAR) and in-hospital mortality in patients with spontaneous intracerebral hemorrhage (ICH) has been established. However, the association with long-term mortality in spontaneous ICH remains unclear. This study aims to investigate the association between FAR and long-term mortality in these patients.

METHODS: Our retrospective study involved 3,538 patients who were diagnosed with ICH at West China Hospital, Sichuan University. All serum fibrinogen and serum albumin samples were collected within 24 h of admission and participants were divided into two groups according to the FAR. We conducted a Cox proportional hazard analysis to evaluate the association …

Toward The Development Of A Pan-Lyssavirus Vaccine, Sabrine Ben Hamed, Jacob Myers, Anisha Chandwani, Christoph Wirblich, Drishya Kurup, Nir Paran, Matthias Schnell

Department of Microbiology and Immunology Faculty Papers

In addition to the rabies virus (RABV), 16 more lyssavirus species have been identified worldwide, causing a disease similar to RABV. Non-rabies-related human deaths have been described, but the number of cases is unknown, and the potential of such lyssaviruses causing human disease is unpredictable. The current rabies vaccine does not protect against divergent lyssaviruses such as Mokola virus (MOKV) or Lagos bat virus (LBV). Thus, a more broad pan-lyssavirus vaccine is needed. Here, we evaluate a novel lyssavirus vaccine with an attenuated RABV vector harboring a chimeric RABV glycoprotein (G) in which the antigenic site I of MOKV replaces …

The Effects Of Psychedelic Microdosing On Mental Health: A Systematic Review, David F. Lo, Hasan Zia, Adarsh Thakur, Praneetha Rajkumar, Don D. Shamilov

Rowan-Virtua Research Day

This poster explores the effects of psychedelic microdosing on mental health conditions. Roughly 5.5 million individuals in the U.S. utilize psychedelics to treat their mental health issues. The primary substances used for microdosing currently include LSD and psilocybin, but mescaline, DMT, and amphetamines are used less commonly. This systematic review included 16 unique articles. The types of articles included: observational, placebo, self-reported, motivational, literature review, and comparative studies. The studies indicated lower levels of anxiety, depression, and stress among those that microdose. However, drawbacks such as difficulty sleeping and headaches were reported. Various studies have been published on the effects …

Advancing Risk Stratification In Hfpef: Unveiling The Potential Of Cardiac Fibrosis Markers For Early Diagnosis And Enhanced Patient Outcomes, Mariam Abdeen

Rowan-Virtua Research Day

Heart failure with preserved ejection fraction (HFpEF) challenges clinicians due to its diverse presentation and limitations in traditional diagnostic criteria. This study delves into the potential of cardiac fibrosis markers like galectin-3, NT-proBNP, and trimethylamine N-oxide (TMAO) to enhance diagnostic precision and patient outcomes in HFpEF. A systematic review of sixteen relevant studies revealed that these biomarkers offer promise for early detection and improved risk assessment. For instance, TMAO indicates systemic implications of HFpEF, while galectin-3 shows predictive value across heart failure types. Additionally, machine-learning models incorporating multiple biomarkers predict significant risk of adverse outcomes. Despite these advances, challenges like …

Efficacy Of Psilocybin In The Treatment Of Substance And Alcohol Use Disorders, Hanna Brancaccio

Rowan-Virtua Research Day

Introduction: Substance use disorder (SUD) and alcohol use disorder (AUD) are major public health crises, affecting millions of Americans. Current treatment options include behavioral therapies and medications. In this review, we explored psilocybin’s efficacy in treating SUD and AUD.

Methods: Key terms were used to search databases to identify articles that addressed psilocybin in the treatment of SUD. Included in the review were indexed, peer-reviewed, primary sources that were published within the last 10 years. Excluded studies were non-peer reviewed, not relevant to the thesis, and did not have an English translation.

Results: The psychodynamic antidepressant effects of psilocybin mark …

Bridging Gaps In Opioid Use Disorder Treatment: Prehospital And Emergency Department Interventions, Quin W. Buob, Zachary J. Noll

Rowan-Virtua Research Day

Since 2011, drug overdose has been the leading cause of accidental death in the United States, with two-thirds of these deaths related to opioid drugs. In 2020, the CDC reported an increase of over 91,000 overdose-related deaths. Also, non-fatal overdoses face a 5.5% one-year mortality rate post discharge, with a significant portion subsequently overdosing within 48 hours.

Access to Buprenorphine/Medication-Assisted Treatment (MAT) has been instrumental in reducing opioid-related mortality by over two-thirds, yet treatment initiation remains significantly low. Limited access stems from socioeconomic disparities and insufficient substance use treatment resources.

Emergency departments (EDs) have pioneered Buprenorphine inductions, showcasing variable success …

Brain Connectivity Pattern Changes Associated With Psychedelic-Assisted Psychotherapy, Prince Patel, Samrat Gollapudi, Brian Joseph Mathew, Bhaumik Patel

Rowan-Virtua Research Day

Psychedelic-assisted psychotherapy (PAP) has shown promising therapeutic benefits for various psychiatric disorders, but the underlying neural mechanisms remain unclear. This study aimed to investigate the effects of psychedelics on brain connectivity patterns using functional magnetic resonance imaging (fMRI). A comprehensive literature search was conducted in PubMed and Google Scholar databases using relevant keywords related to psychedelics, connectivity, therapy, and fMRI. Only studies involving major psychedelic compounds (LSD, psilocybin, ayahuasca) and measuring outcomes via fMRI were included.

The findings from the reviewed studies suggest that psychedelics induce acute disruptions in normal large-scale brain network patterns, leading to a compromised modular but …

The Impact Of Vitamin Supplementation (D, B12, B9) On Behaviors Associated With Autism Spectrum Disorder, Rohan Mehra

Rowan-Virtua Research Day

Background: One in 36 children in the United States are diagnosed with Autism Spectrum Disorder (ASD). Although heritability of the condition ranges from 40 to 80%, other factors such as vitamin levels, may have a significant impact on the risk of development. These vitamins include D, B12, and B9.

Purpose: To assess the impact vitamin supplementation has on behaviors associated with ASD, and to determine which specific aspects of ASD may be improved with vitamin supplementation.

Methods: A literature review was performed. The search was utilized PubMed, JSTOR and Web of Science. Keyword strings included: “Vitamin D B12 B9 folate …

Soluble Antimicrobial Peptide (Amp) Screening To Rationally Design Amp-Hydrogels That Selectively Prevent Biofilm Formation, Matthias Recktenwald, Muskanjot Kaur, Mohammed M. Benmassaoud, Aryanna Copling, Tulika Khanna, Michael Curry, Denise Cortes, Gilbert Fleischer, Valerie J. Carabetta, Sebastián L. Vega

Rowan-Virtua Research Day

Staphylococcus aureus is an opportunistic pathogen that lives on surfaces and skin and can cause serious infections once inside the body. While antibiotics effectively kill bacteria, there are a growing number of infections with antibiotic-resistant strains. Antimicrobial peptides (AMPs) are part of the innate immune system and can eliminate pathogens including bacteria, fungi, and viruses, and are a promising alternative to antibiotics. Although studies have reported that AMP-functionalized hydrogels can prevent bacterial adhesion and biofilm formation, these materials generally consist of one AMP at an arbitrary concentration, and AMP dosing and the combined effects of multiple AMPs are not well …

Evaluation Of The Efficacy Of Novel Drugs And Combinations Against Extensively- And Pan-Drug Resistant Acinetobacter Baumannii Isolates, Keertana Jonnalagadda, Rachel Carr, Valerie Carabetta

Rowan-Virtua Research Day

Acinetobacter baumannii, a Gram-negative, nosocomial, opportunistic pathogen is commonly infectious in immunocompromised patients. More specifically patients develop healthcare-associated infections (HAI) spanning beyond sepsis, pneumonia, meningitis, and urinary tract infections. Due to its rapid ability to acquire antibiotic resistance, it has raised the necessity to discern a novel therapeutic treatment that can be effectively used against the multidrug resistant (MDR) A. baumannii. Cooper University Hospital (CUH) faced an increased case load of patients that were infected with MDR A. baumannii. The patient isolates obtained from CUH were highly resistant to the 22 standard-of-care antibiotics. With the recent introduction …

Sdrnas Participate In The Maintenance And Onset Of Prostate Cancer, Neil Chaudhary

Poster Presentations

What is an sdRNA? Noncoding RNA (ncRNA) is a class of RNA that includes microRNA (miRNA) and small nucleolar RNA (snoRNA). Fragments excised from ncRNAs are known as noncodingderived RNA (ndRNA). A certain class of ndRNAs that are derived from snoRNAs have been denoted as Small Nucleolar Derived RNAs (sdRNAs). Our lab has previously hypothesized and demonstrated that sdRNAs display regulatory functions on target genes, similar to the functions of miRNAs. sdRNAs are almost identical to microRNAs and differ mainly in their source of origin.

Our lab has shown that sdRNA-93 is frequently misexpressed in breast cancer cell lines and …

Incidence Of Rapidly Progressive Osteoarthritis Following Intra-Articular Hip Corticosteroid Injection: A Systematic Review And Meta-Analysis, Franco M. Sabatini, Anna Cohen-Rosenblum, Travis B. Eason, Charles P. Hannon, Samuel D. Mounce, Chad A. Krueger, F Winston Gwathmey, Stephen T. Duncan, David C. Landy

School of Medicine Faculty Publications

BACKGROUND: The American Academy of Orthopedic Surgery recommends intra-articular corticosteroid injections (CSIs) for managing hip osteoarthritis (OA) based on short-term, prospective studies. Recent retrospective studies have raised concerns that CSIs may lead to rapidly progressive OA (RPOA). We sought to systematically review the literature of CSIs for hip OA to estimate the incidence of RPOA. METHODS: MEDLINE, Embase, and Cochrane Library were searched to identify original research of hip OA patients receiving CSIs. Overall, 27 articles involving 5831 patients published from 1988 to 2022 were included. Study design, patient characteristics, CSI details, follow-up, and cases of RPOA were recorded. Studies …

Dietary Analysis For Hashimoto’S Thyroiditis: An Integrative Review, Evan Thompson, Alison Hultquist

Master of Science in Nursing Final Projects

Abstract

Hashimoto’s Thyroiditis (HT) is the leading cause of primary hypothyroidism in the United States. In HT, there is an infiltration by lymphocytes which leads to the production of autoantibodies against the thyroid gland. Throughout this integrative review, the aim was to evaluate the effectiveness of micronutrient supplementation and dietary management as adjunct treatments in HT. The purpose was to assist primary care providers in the development of a more holistic plan of care. Literature published within the past seven years was gathered and reviewed from PubMed, CINAHL, and Cochrane Library. Findings indicate that many patients with HT may benefit …

Rod-Specific Downregulation Of Omega-3 Very-Long-Chain Polyunsaturated Fatty Acid Pathway In Age-Related Macular Degeneration, William C. Gordon, Marie Audrey I. Kautzmann, Bokkyoo Jun, Megan L. Cothern, Zhide Fang, Nicolas G. Bazan

School of Medicine Faculty Publications

Docosahexaenoic acid (DHA; 22:6) plays a key role in vision and is the precursor for very-long-chain polyunsaturated fatty acids (VLC-PUFAs). The release of 32- and 34-carbon VLC-PUFAs and DHA from sn-1 and sn-2 of phosphatidylcholine (PC) leads to the synthesis of cell-survival mediators, the elovanoids (ELVs) and neuroprotectin D1 (NPD1), respectively. Macula and periphery from age-related macular degeneration (AMD) donor retinas were assessed for the availability of DHA-related lipids by LC-MS/MS-based lipidomic analysis and MALDI-molecular imaging. We found reduced retina DHA and VLC-PUFA pathways to synthesize omega-3 ELVs from precursors that likely resulted in altered disks and photoreceptor loss. Additionally, …

Correlation Between Gut Biomarkers And Depression, Jianle Gao

Rowan-Virtua Research Day

The correlation between the gut-microbiota- brain axis and mental state in the context of mental disorders such as Major Depressive Disorder (MDD), Schizophrenia, etc. has been well studied. Production of inflammatory and non-inflammatory metabolites by the gut- microbiota directly and indirectly affects the brain and mood. Therefore, colonization by maladaptive, pro-inflammatory bacteria may cause mood dysregulation and depressive features. Metabolites from these bacteria can be quantitatively analyzed for use as biomarkers of Major Depressive Disorder. Biomarkers studied include: serotonin, dopamine, butyrate, acetate, and propionate.

Maldi-Tof Ms Based Proteomic Fingerprinting Of Total Serum Plasma For Somatic Pain Syndromes, Isaiah Pinkerton, Venkateswar Venkataraman

Rowan-Virtua Research Day

There are racial and ethnic disparities regarding pain management within the United States, and that disproportionately affects women of color. There is also a fundamental lack of information regarding the biological mechanism by which pain sensitization and perception occurs, and how it could be affected by both neurologic and somatic pain syndromes.

Methods: Research was performed on principal electronic scientific databases including Google Scholar, PubMed, and Embase with search terms “MALDI-TOF”, “ESI-MS”, “Pain”, and “Biomarkers”, as well as other modifiers to narrow the literature search.

Results: Studies on comparison between MALDI-TOF and other traditional analysis platforms, including Electrospray Ionization (ESI-MS), …

The Developing Effects Of Potassium Ferricyanide On Tetrahymena, Katelyn Coronell

Whittier Scholars Program

Potassium Cyanide is a highly toxic chemical asphyxiant that interferes with the body's ability to use oxygen, typically by directly affecting the body by ingestion, inhalation, skin contact, or eye contact(CDC, 2011). Due to its high toxicity, the main effect that leads to the downfall of the organism begins with the cessation of aerobic metabolism; it does this by cyanide binding to the ferric ions and inhibiting cytochrome oxidase within the mitochondria (Zhang, 2015). There are no physical dangers the substance causes. Although, there are many chemical dangers. If used at temperatures higher than 70℉ The substance may produce toxic …

Investigation Into The Potential For Acquired Cross Tolerances Of Amphetamines, Benjamin Weldon

CMC Senior Theses

In the United States, the treatment of ADHD through use of psychostimulants in adolescents is a growing reality that many people know today and many more will know in the coming years. Although the effectiveness of psychostimulants is a known asset, the benefits of these medications may not be a permanent solution, suggesting not only the presence of a tolerance build up, but as many stimulants are prescribed in a joint effort to combat ADHD, a possible cross tolerance between two prescribed medications. There are minimal studies published that have addressed the topic of cross stimulation tolerance buildup between prescription …

A Quality Improvement Project To Improve Management Of Urinary Tract Infections In A System Of Pediatric Urgent Care Centers, Benjamin Klick, Tammy Speerhas, Jessica Parrott, Jeffrey Bobrowitz, Anne Mcevoy, Debra Conrad, Theresa Guins

Ellmer School of Nursing Faculty Publications

Background and objective: Urinary tract infections (UTIs) are a common problem in pediatric urgent care medicine. There are multiple quality improvement (QI) projects related to the management of UTIs documented in the pediatric literature. We developed a project to decrease the prescribing of ultimately unneeded antibiotics for possible UTIs in a pediatric urgent care setting. A similar project has not been described in the pediatric literature.

Methods: We first reviewed the charts of patients presenting to a system of pediatric urgent care centers with a possible UTI over a 2-year period. We then launched a QI project with three plan, …

Sugar-Sweetened Beverages Intake, Abdominal Obesity, And Inflammation Among Us Adults Without And With Prediabetes—An Nhanes Study, Wei Ting Lin, Yu Hsiang Kao, Mirandy S. Li, Ting Luo, Hui Yi Lin, Chien Hung Lee, David W. Seal, Chih Yang Hu, Lei Shih Chen, Tung-Sung Tseng

School of Public Health Faculty Publications

Excessive sugar-sweetened beverages (SSB) consumption and abdominal obesity have been independently linked to numerous disorders, including diabetes and elevated C-reactive protein (CRP). This study aimed to explore the association between SSB intake, abdominal obesity, and inflammation in normal and prediabetic adults. Sugar intake from SSBs was calculated from 24-h dietary recalls and further classified into non-, medium-, and high-intake. The status of non- and prediabetes was identified based on hemoglobin A1c level. All analyses were performed under a survey module with appropriate sampling weights to control for the complex survey design. A total of 5250 eligible adults without diabetes were …

Thromboelastography Profiles Of Hemophilia A Patients On Emicizumab, Daniel J. Vanzweden, Meera Chitlur, Charity J. Stadler

Medical Student Research Symposium

Emicizumab is a new monoclonal antibody developed to dtreat people with Hemophilia A, especially those with antibodies. However, breakthrough bleeding can still occur in patients taking Emicizumab. TEG is a global coagulation assay which measures coagulability through viscosity. This study describes the use of tissue factor activated TEG in measuring bleeding profiles in patients taking Emicizumab. The goal of this prospective study is to determine if TEG can be used, which variables of TEG might be useful, and how much more useful it is than the current standard, aPtt. Findings include a 25% increased R time and 24% increased K …

Updates In The Pharmacologic Prophylaxis And Treatment Of Invasive Candidiasis In The Pediatric And Neonatal Intensive Care Units, James Hunter Fly, Seerat Kapoor, Kelly Bobo, Jeremy S. Stultz

Faculty Publications

Purpose of review The goal of this review was to provide an update on the prevention and treatment options for invasive candidiasis (IC) in the neonatal intensive care unit (NICU) and pediatric intensive care unit (PICU).

Recent findings Studies have further validated the use of fluconazole for IC prophylaxis among high-risk patients in the NICU. It remains unclear if prophylaxis leads to resistance development and the ideal dosage regimen is still not clear. Recent studies have been published comparing caspofungin and micafungin to amphotericin B and illustrated similar efficacy outcomes in the NICU. Micafungin now has approval from the United …

Transversus Abdominis Plane Block: A Scoping Review, Liam Maher, Leanne Orians, Gabrielle Pappas, Lanny Coker Dnsc, Crna

Doctor of Nursing Practice Projects

The purpose of this project is to provide an overview of the literature on the analgesic effects of transverse abdominal plane (TAP) block and its effectiveness in reducing opioid consumption.

Pain Control: Opioid Vs. Nonopioid Analgesia During The Immediate Postoperative Period, Shamsie M. Lumpkin Bsn, Srna, Isaac W. Parrish Bsn, Srna, Austin S. Terrell Bsn, Srna, Dwayne S. Accardo Dnp, Aprn, Crna

Doctor of Nursing Practice Projects

Background Opioid analgesia has become the mainstay for acute pain management in the postoperative setting. However, the use of opioid medications comes with significant risks and side effects. Due to increasing numbers of prescriptions to those with chronic pain, opioid medications have become more expensive while becoming less effective due to the buildup of patient tolerance. The idea of opioid-free analgesic techniques has rarely been breached in many hospitals. Emerging research has shown that opioid-sparing approaches have resulted in lower reported pain scores across the board, as well as significant cost reductions to hospitals and insurance agencies. In addition to …

Mutational And Biophysical Robustness In A Prestabilized Monobody, Peter G. Chandler, Li Lynn Tan, Benjamin T. Porebski, James S. Green, Blake T. Riley, Sebastian S. Broendum, David E. Hoke, Robert J. Falconer, Trent P. Munro, Malcolm Buckle, Colin J. Jackson, Ashley M. Buckle

Advanced Science Research Center

The fibronectin type III (FN3) monobody domain is a promising non-antibody scaffold, which features a less complex architecture than an antibody while maintaining analogous binding loops. We previously developed FN3Con, a hyperstable monobody derivative with diagnostic and therapeutic potential. Prestabilization of the scaffold mitigates the stability–function trade-off commonly associated with evolving a protein domain toward biological activity. Here, we aimed to examine if the FN3Con monobody could take on antibody-like binding to therapeutic targets, while retaining its extreme stability. We targeted the first of the Adnectin derivative of monobodies to reach clinical trials, which was engineered by directed evolution for …