Pharmacy and Pharmaceutical Sciences Commons^™

Modulation Of Hypoxia-Induced Chemoresistance To Polymeric Micellar Cisplatin: The Effect Of Ligand Modification Of Micellar Carrier Versus Inhibition Of The Mediators Of Drug Resistance, Hoda Soleymani Abyaneh, Amir Hassan Soleimani, Mohammad Reza Vakili, Rania Soudy, Kamaljit Kaur, Francesco Cuda, Ali Tavassoli, Afsaneh Lavasanifar

Pharmacy Faculty Articles and Research

Hypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two strategies for the modulation of HICR against cisplatin micelles: a) the development of actively targeted micelles; and b) combination therapy with modulators of HICR in MDA-MB-231 cells. Actively targeted cisplatin micelles were prepared through surface modification of acetal-poly(ethylene oxide)-poly(-carboxyl-"-caprolactone) (acetal-PEO-PCCL) micelles with epidermal growth factor receptor (EGFR)-targeting peptide, GE11 (YHWYGYTPQNVI). Our results showed that hypoxia induced resistance against free and …

The Smarxt Media Literacy Program: Improving Evidence-Based Prescribing Among Medical Students, Bethany D. Corbin, Jason B. Colditz, Galen E. Switzer, Jaime E. Sidani, Patricia M. Klatt, Ted Schaffer, Brian A. Primack

Journal of Media Literacy Education

Many prescriptions written are not evidence-based, resulting in unnecessary morbidity and mortality. Media literacy may help medical trainees optimize evidence-based decision-making. In this study, we aimed to assess feasibility, acceptability, and initial efficacy of a media literacy prescribing program. We recruited 30 medical students, who completed animated video modules about pharmaceutical marketing and prescribing. We used a process evaluation and open-ended items to assess feasibility and acceptability, and knowledge tests before and after the intervention to assess efficacy. The program was feasible to implement and well-accepted. Knowledge and attitude targets around evidence-based prescribing and drug marketing improved after the intervention.

Impact Of The Use Of Local Fidaxomicin Treatment Algorithms For Managing Clostridium Difficile Infection In Hospitalized Patients In Southeastern United States, Jonathan C. Cho, Sandy J. Estrada, Jamie J. Kisgen, Angelina Davis, Laura Puzniak

Pharmacy Faculty Publications and Presentations

Background: Clostridium difficile-associated diarrhea (CDAD) is a major public health threat that results in increased length of stay, hospital readmissions, deaths, and economic burden. CDAD treatment is often guided by severity of disease. Although various tools exist to determine CDAD severity, real-world data evaluating the use of such tools in treatment algorithms are sparse. Methods: A local CDAD treatment pathway was developed independently to guide fidaxomicin prescribing at wellStar Health System (WellStar) and at Lee Health (LH) and Sarasota Memorial Hospital (SMH). Each algorithm was designed locally by the stewardship pharmacist and was utilized to identify patients at high risk …

Special Topics In Emerging Contaminants Php 579, Joanna Burkhardt

Library Impact Statements

No abstract provided.

Use Of Virtual Games For Interactive Learning In A Pharmacy Curriculum, Jerika Lam, Mary Gutierrez, Jeff A. Goad, Larisa Odessky, Jason Bock

Pharmacy Faculty Articles and Research

Background and purpose: To evaluate student pharmacists’ attitudes and satisfaction toward playing educational virtual games in the classroom.

Educational activity and setting: The study setting was playing virtual games in the classroom setting. First year student pharmacists participated in two Mimycx quests in the Healthcare Communication and the Psychiatry/Neurology courses. Students were randomly assigned into teams and worked together to complete the assigned quest games. Completion of the pre- and post-quest questionnaires via Qualtrics was voluntary.

Findings: A total of 79 student pharmacists played the Mimycx quests. Only 66 students completed both pre- and post-quest questionnaires. Students …

Cervical Ripening For Induction Of Labor, Deb Sepulveda, Michael G. Pinette, Heidi Morin, Colette Dumais, Sarah Austin, Hector Tarraza, Maria Tkacz, Zander Abbott

MaineHealth Maine Medical Center

Decrease in Cervidil use for cervical ripening by 20% of anticipated doses prior to Dec 1, 2018 (6 mos) , with a potential for cost savings = 40 doses x approx. $2000/dose = $80,000.

In Vitro And Ex-Vivo Evaluation Of Topical Formulations Designed To Minimize Transdermal Absorption Of Vitamin K1, Ramina Nabiee, Barent Dubois, Laura Green, Ajay Sharma, Siu Fun Wong, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

Topical application of Vitamin K1 has been demonstrated to effectively treat papulopustular skin rash, a serious and frequently encountered side effect of Epidermal Growth Factor Inhibitors (EGFRIs). Systemic absorption of vitamin K1 from skin and the resultant consequence of antagonizing EGFRIs anticancer effects jeopardizes the clinical acceptability of this rather effective treatment. The purpose of the present study was to rationally formulate and evaluate the release rate and transdermal absorption of a wide range of Vitamin K1 dermal preparations with a variety of physiochemical properties. A library of 33 formulations with were compounded and tested for Vitamin K1 permeation using …

Determination Of Pyrrolizidine Alkaloids In Dietary Sources Using A Spectrophotometric Method, Oana C. Șeremet, Octavian T. Olaru, Mihaela Ilie, Claudia M. Guțu, Mihai G. Nițulescu, Camelia Diaconu, Catalina Motofei, Denisa Margină, Simona Negreș, Cristina E. Zbârcea, Emil Ștefănescu

Journal of Mind and Medical Sciences

Pyrrolizidine alkaloids (PAs) are a class of toxic compounds found in the composition of more than 6000 plants. People can be exposed to PAs by consuming phytotherapeutic products, food from crops contaminated with seeds of some species with high content of PAs, and/ or contaminated animal products like bee products. For this reason we developed and validated a method for quantitative determination of PAs, from the most frequently contaminated food sources, honey and flour. Colorimetric Ehrlich reagent method was used with standard addition (1mg/kg senecionine). The extraction solvent was methanol 50% acidified with citric acid to pH 2-3, as this …

Hptlc Assay Of Nicotine And Cotinine In Biological Samples, Ana Maria Vlasceanu, Daniela Luiza Baconi, Anne Marie Ciobanu, Vlad D. Constantin, Liana Ples, Cristian Balalau, Miriana Stan

Journal of Mind and Medical Sciences

This study presents the development of a simple high-performance thin layer chromatography (HPTLC) method for the determination of nicotine and its metabolite cotinine in human plasma and urine.

The following mobile phases: methanol: ammonia (100:1.5, v:v), chloroform: acetone: ammonia (48.75: 48.75: 2.5, v:v:v), methanol: chloroform: ammonia (48.75: 48.75: 0.5, v:v:v) and glass plates precoated with silicagel 60 F254 (20x20) as a stationary phase were used. Densitometric scanning was performed at 263 nm. Two different extraction procedures have been applied: liquid-liquid extraction using dichloromethane at alkaline pH and solid-phase extraction using C18 cartridges.

Preliminary tests in order to establish the system …

The Switch From Patented Medicine To The Generic One: An Option Or A Necessity?, Păduraru Dan Nicolae, Ion Daniel, Nica Adriana Elena, Coman Florentina, Coțofană Marius, Badiu Dumitru Cristinel, Grigorean Valentin Titus, Bolocan Alexandra, Andronic Octavian

Journal of Mind and Medical Sciences

This paper assesses the influence of a number of factors taken into account when a brand name drug is replaced by a generic one. It also evaluates responses of health professionals – physicians and pharmacist—and patients regarding the issue of switching. We compared and contrasted their responses in order to identify new points of cooperation for the intended benefit of the patient. Thus, the sample drew from all three groups, consisting of 50 doctors, 50 pharmacists, and 50 patients. We collected information regarding the age, residence, income level, and education level for the patients, and age and experience for the …

New Oral Anticoagulants And Their Reversal Agents, Crista L. Laslo, Anca Pantea Stoian, Bogdan Socea, Dan N. Paduraru, Oana Bodean, Laura I. Socea, Tiberiu P. Neagu, Ana Maria Alexandra Stanescu, Dragos Marcu, Camelia C. Diaconu

Journal of Mind and Medical Sciences

Atrial fibrillation is a commonly encountered pathology in medical practice, and its prevalence has shown a continuous rise over the past years. Atrial fibrillation has a significant impact on patients' quality of life, not only due to the standard anticoagulant treatment with vitamin K antagonists that require close monitoring and dose adjustment, but also due to the fragile equilibrium between hemorrhagic and thrombotic risks. The introduction of new oral anticoagulants (NOACs) in the treatment guidelines for atrial fibrillation has improved the quality of life, as NOACs do not require close monitoring or dose adjustments. However, even if the safety profile …

Increase Referrals To Medaccess At The Smhc Pharmacy, Sarah Jones, Kim Beaudoin

Southern Maine Health Care

Problem/Impact Statement: The MedAccess Program is losing referrals at point of sale in the SMHC Pharmacy.

Scope: Patients who are currently serviced by the SMHC Pharmacy that are uninsured or under insured and meet the % Federal Poverty Level for prescription assistance.

Correcting Glucose-6-Phosphate Dehydrogenase Deficiency With A Small-Molecule Activator, Sunhee Hwang, Karen Mruk, Simin Rahighi, Andrew G. Raub, Che-Hong Chen, Lisa E. Dorn, Naoki Horikoshi, Soichi Wakatsuki, James K. Chen, Daria Mochly-Rosen

Pharmacy Faculty Articles and Research

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the …

Development Of Novel Intramolecular Fret-Based Abc Transporter Biosensors To Identify New Substrates And Modulators, Bremansu Osa-Andrews, Kee W. Tan, Angelina Sampson, Surtaj H. Iram

Chemistry and Biochemistry Faculty Publications

Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and modulators of MRP1 by exploiting intramolecular fluorescence resonance energy transfer (FRET), we genetically engineered six different two-color MRP1 proteins by changing green fluorescent protein (GFP) insertion sites, while keeping the red fluorescent protein (RFP) at the C-terminal of MRP1. Four of six recombinant proteins showed normal expression, localization, and transport activity. We quantified intramolecular FRET using ensemble …

The 340b Program, Contract Pharmacies And Hospitals: An Examination Of The First 25 Years Of Their Increasingly Complex Relationship, David P. Paul Iii, Morgan Cathlene Ludado, Morgan Ruley, Hannah Sayre, Alberto Coustasse

Management Faculty Research

The 340B Drug Pricing Program, created by Congress in 1992 through the Veterans Health Care Act, has provided discounted drug prices to hospitals and other health care organizations serving a wide population of low-income patients. Some 340B programs use contract pharmacies, an arrangement whereby the hospital or health care organization signs a contract directly with a pharmacy to provide covered pharmacy services at discounted prices.

The federal 340B Drug Pricing Program has provided access to reduced price prescription drugs to over 35,000 individual healthcare facilities and sites certified by the U.S. Department of Health and Human Services (HHS), and clinics …

Integration Of A Pharmacist In A Pediatric Medical Home For Children With Medical Complexity, Alannah K. Yoder, Richard K. Ogden Jr., Ingrid A. Larson, Emily J. Goodwin

Pharmacy Posters

Background/Objectives

Children with medical complexity require unique care, specialized attention, and a dedicated team to meet the needs of the patient & caregivers. Drug-therapy related problems in complex, chronic conditions influence financial, institutional, and patient outcomes. The addition of a pharmacist allows for collaboration and delivery of comprehensive medication management in order to provide value-added medication services to optimize complex therapeutic regimens and patient outcomes through evidence-based practice, medication adherence, medication use coordination, and medication safety processes.

Description

Our program provides a pediatric medical home for hundreds of children with medical complexity. Families are cared for by a comprehensive …

Evaluation Of Processes And Procedures For Care Of The Opioid Recipient Patient In The Primary Care Setting, Anne Sproat

Doctoral Projects

Introduction: Chronic non-cancer pain is far reaching, affecting over 100 million Americans (Zgierska et al., 2018). Opioids are commonly prescribed for chronic pain, with approximately 20% of patients presenting to primary care offices with symptoms of pain or pain-related diagnoses (Dowell, Haegerich, & Chou, 2016). As a result, opioid prescribing rates are increasing at a faster rate for primary care practice compared with other specialties (Dowell et al., 2016). Within the United States population, it is estimated that three percent to four percent of the adult population are prescribed long-term opioids for the treatment of chronic non-cancer pain (Dowell et …

Increasing Bedside Medication Safety In An Intensive Care Setting, Natasha Stankiewicz, Jonathan Archibald, Scu 2, Mark Parker, Stephen Tyzik, Suneela Nayak, Ruth Hanselman, Amy Sparks

Operations Transformation

A PERFORMANCE IMPROVEMENT PROJECT FOR INCREASED BEDSIDE MEDICATION SAFETY

The convenience of having certain medications directly available at bedside has long been a priority for a medical intensive care nursing team in an academic tertiary medical center.

However, it was apparent to new staff and leadership that there was a lack of awareness and interest in securing medications within the department. This posed a risk to patients, families, visitors and colleagues.

Baseline metrics on patient safety were collected and a root cause analysis was conducted. Countermeasures included increased education of medication safety as well as a instituting a KPI which …

The Role Of Cdk8 In Metastatic Growth Of Colon Cancer, Jiaxin Liang

Theses and Dissertations

Unresectable hepatic metastases of colon cancer poorly respond to existing therapies and are a major cause of colon cancer lethality. Transcription- regulating Mediator kinase CDK8, an early clinical stage drug target, is amplified or overexpressed in many colon cancers and CDK8 expression correlates with shorter patient survival. Here we show that CDK8 inhibition does not generally suppress proliferation of CDK8-overexpressing colon cancer cells but nevertheless CDK8 knockdown by shRNA or CDK8 kinase inhibition by a selective small-molecule drug candidate suppresses metastatic growth of mouse and human colon cancer cells in the liver. This effect is due at least in part …

Structure-Activity Profiling Of Alkaloid Natural Product Pharmacophores Against A Schistosoma Serotonin Receptor, Jonathan S. Marchant, Wayne W. Harding, John D. Chan

Publications and Research

Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscularfunctionto sexualmaturationandegglaying. Intheparasiticblood flukeSchistosomamansoni,5-HTtargets several G-protein coupled receptors (GPCRs), one of which has been demonstrated to couple to cAMP and regulate parasite movement. This receptor, Sm.5HTRL, has been successfully co-expressed in mammalian cells alongside a luminescent cAMP-biosensor, enabling pharmacological profiling for candidate anti-schistosomal drugs. Here, we have utilized this assay to perform structure-activity investigations of 143 compounds containing previously identified alkaloid natural product pharmacophores (tryptamines, aporphines and protoberberines) shown to regulate Sm.5HTRL. These experiments mapped regions of the tryptamine pharmacophore amenable and intolerant to substitution, highlighting …

Epidemiology Of Diabetic Foot Infection In The Metro-Detroit Area With A Focus On Independent Predictors For Pathogens Resistant To Recommended Empiric Antimicrobial Therapy, Oryan Henig, Jason M. Pogue, Raymond Cha, Paul E. Kilgore, Umar Hayat, Mahmoud Ja'ara, Raza Muhamad Ali, Salman Mahboob, Rahul Pansare, Kathryn Deeds, Bushra Joarder, Hyndavi Kandala, Sorabh Dhar, Keith S. Kaye

Department of Pharmacy Practice

Background. The polymicrobial nature of diabetic foot infection (DFI) and the emergence of antimicrobial resistance have complicated DFI treatment. Current treatment guidelines for deep DFI recommend coverage of methicillin-resistant Staphylococcus aureus (MRSA) and susceptible Enterobacteriaceae. This study aimed to describe the epidemiology of DFI and to identify predictors for DFI associated with multidrug-resistant organisms (MDROs) and pathogens resistant to recommended treatment (PRRT).

Methods. Adult patients admitted to Detroit Medical Center from January 2012 to December 2015 with DFI and positive cultures were included. Demographics, comorbidities, microbiological history, sepsis severity, and antimicrobial use within 3 months before DFI were obtained …

Pediatric Obesity: Influence On Drug Dosing And Therapeutics, Barbara Ameer Pharmd, Mba, Bcps, Fcp, Michael Weintraub Md

Department of Medicine Faculty Papers

Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of US children and adolescents. Severe obesity (³120% of the 95^th percentile of BMI-for-age, or a BMI of ³35 kg/m²) is the fastest growing subgroup and now approaches 6% of all US youth. Health consequences (e.g., type 2 diabetes, coronary heart disease) are related in a dose-dependent manner to severity of obesity. Since therapeutic interventions are less effective in severe obesity, prevention is a high priority.

Treatment plans involving combinations of …

Stability And Compatibility Of Diphenhydramine Hydrochloride In Intravenous Admixtures: A New Look At An Old Drug, Daniel Sabins, Tuong Diep, Pamela Mccartan, Shashi Patel, Fang Zhao

Doctoral External Publications

Purpose: Intravenous (IV) admixtures of diphenhydramine are widely used in hospitalized patients to prevent or treat hypersensitivity reactions. However, there is limited data to support the admixture preparation in this manner. This study was designed to investigate the stability and compatibility of diphenhydramine in IV admixtures with a goal to establish a 14-day beyond-use dating with storage under refrigeration. Methods: The commercially available 50 mg/mL diphenhydramine hydrochloride injection vials were used to prepare the 0.2 and 1.0 mg/mL IV admixtures in 0.9% sodium chloride injection and 5% dextrose injection in 50 mL polyvinyl chloride (PVC) bags. The IV bags were …

Formulation, Characterization And Evaluation Of Morusin Loaded Niosomes For Potentiation Of Anticancer Therapy, Srishti Agarwal, M. Sheikh Mohamed, Sreejith Raveendran, Ankit K. Rochani, Toru Maekawa, D. Sakthi Kumar

College of Pharmacy Faculty Papers

Morusin, a water-insoluble prenylated flavonoid is known for its numerous medicinal properties. It manifests its anticancer potential by suppression of genes involved in tumor progression. However, poor solubility of the drug results in low bioavailability and rapid degradation thus hindering its clinical utilization. In order to overcome this, we have synthesized a niosome system composed of non-ionic surfactant span 60 and cholesterol using a thin-layer evaporation technique to improve the aqueous-phase solubility of the drug. Highly cytocompatible niosomes of 479 nm average size with smooth and uniform spherical morphology were synthesized in a facile manner. Unlike free morusin, nanomorusin was …

Gaw20: Methods And Strategies For The New Frontiers Of Epigenetics And Pharmacogenomics, Nathan L. Tintle, David W. Fardo, Marzia De Andrade, Stella Aslibekyan, Julia N. Bailey, Justo Lorenzo Bermejo, Rita M. Cantor, Saurabh Ghosh, Philip Melton, Xuexua Wang, Jean W. Maccluer, Laura Almasy

Biostatistics Faculty Publications

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual …

Methods For Treating Neuropathic Pain, Joseph R. Holtman, Peter Anthony Crooks, Linda Phyliss Dwoskin, Michael J. Mcintosh, Elzbieta Pogonowska Wala

Pharmaceutical Sciences Faculty Patents

Provided are methods for using bis-quaternary ammonium compounds to treat inflammatory pain, neuropathic pain and nociceptive pain.

Ubiquitin Receptor Rpn13 Mediates The Inhibitory Interaction Of Diphenyldihaloketones Clefma And Ef24 With The 26s Proteasome, Geeta Rao, Gregory Nkepang, Jian Xu, Hooman Yari, Hailey Houson, Chengwen Teng Pharm.D., Ph.D., Vibhudutta Awasthi

Faculty Publications

The proteasome is a validated target in drug discovery for diseases associated with unusual proteasomal activity. Here we report that two diphenyldihaloketones, CLEFMA and EF24, inhibit the peptidase activity of the 26S proteasome. The objective of this study was to investigate interaction of these compounds with the proteasome and identify a putative target within the protein components of the 26S proteasome. We employed standard fluorogenic peptide-based proteasome activity assay for trypsin-like, chymotrypsin-like, and caspase-like activities of human purified 26S proteasome in cell-free conditions. GFPu-1 and HUVEC cells were used as proteasome reporter cells. Direct binding studies used purified 19S, 20S, …

Brain Endothelial Erythrophagocytosis And Hemoglobin Transmigration Across Brain Endothelium: Implications For Pathogenesis Of Cerebral Microbleeds, Rudy Chang, Juan Castillo, Alexander C. Zambon, Tatiana B. Krasieva, Mark J. Fisher, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Peripheral endothelial cells are capable of erythrophagocytosis, but data on brain endothelial erythrophagocytosis are limited. We studied the relationship between brain endothelial erythrophagocytosis and cerebral microhemorrhage, the pathological substrate of MRI-demonstrable cerebral microbleeds. To demonstrate the erythrophagocytic capability of the brain endothelium, we studied the interactions between brain endothelial cells and red blood cells exposed to oxidative stress in vitro, and developed a new in vitro cerebral microbleeds model to study the subsequent passage of hemoglobin across the brain endothelial monolayer. Using multiple approaches, our results show marked brain endothelial erythrophagocytosis of red blood cells exposed to oxidative stress compared …

Interfering With Dna Decondensation As A Strategy Against Mycobacteria, Enzo M. Scutigliani, Edwin R. Scholl, Anita E. Grootemaat, Sadhana Khanal, Jakub A. Kochan, Przemek M. Krawczyk, Eric A. Reits, Atefeh Garzan, Huy X. Ngo, Keith D. Green, Sylvie Garneau-Tsodikova, Jan M. Ruijter, Henk A. Van Veen, Nicole N. Van Der Wel

Pharmaceutical Sciences Faculty Publications

Tuberculosis is once again a major global threat, leading to more than 1 million deaths each year. Treatment options for tuberculosis patients are limited, expensive and characterized by severe side effects, especially in the case of multidrug-resistant forms. Uncovering novel vulnerabilities of the pathogen is crucial to generate new therapeutic strategies. Using high resolution microscopy techniques, we discovered one such vulnerability of Mycobacterium tuberculosis. We demonstrate that the DNA of M. tuberculosis can condense under stressful conditions such as starvation and antibiotic treatment. The DNA condensation is reversible and specific for viable bacteria. Based on these observations, we hypothesized …

Epigenetic Biomarkers For Alzheimer’S Disease Using A Transgenic Porcine Model, Yoon Hee Cho

University Grant Program Reports

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for approximately 60~70% of dementia cases. AD afflicts more than 35.6 million individuals worldwide and is expected to increase to 65.7 million by 2030 and 115.4 million by 2050 ¹; AD is a serious public health problem that is causing increased health care costs worldwide. Typically, AD is a relentlessly progressive disorder that initially manifests as severe loss of memory, particularly episodic memory.² The disorder is not curable at present, and the mechanisms driving development of AD are not fully understood. Therefore, there is an urgent need …