Tuberculoma Presenting As Paradoxical Iris In A Hiv Positive Patient, Dr. Supritha Chintamaneni, Dr.Rajendra Prasad S, Dr.Bhanukumar M, Dr.Adarsh L S

Digital Journal of Clinical Medicine

No abstract provided.

Evaluating The Impact Of Verigene® Organism Identification On Antimicrobial Stewardship Recommendations, Rebecca Gerske

Undergraduate Honors Thesis Collection

Verigene® is one of many commercially available rapid diagnostic tests (RDT) for organism identification in blood culture. Community Health Network (CHNw) utilizes this system to identify blood cultures and guide antimicrobial therapy. As antibiotic resistance becomes more and more prevalent, limiting exposure to broad-spectrum antibiotic therapy is of paramount importance. RDT provides more timely information to providers, which if utilized appropriately, can result in the patient receiving appropriate antibiotic therapy in a shorter time and further limits unnecessary antibiotic exposure. This study was a three-part, retrospective chart review to determine the microbiological accuracy of Verigene® within CHNw and evaluate the …

Development Of Gamma-Aminobutyric Acid Nanoemulsions For Dermal Delivery, Kamonwan Singpanna

Chulalongkorn University Theses and Dissertations (Chula ETD)

The aims of this work were to study the effect of the penetration enhancer on physical properties of GABA-loaded nanoemulsions, to evaluate their physical and chemical stabilities and to compare in vitro skin permeability between GABA loaded-nanoemulsions with and without the penetration enhancer. In this study, 1,8-cineole was used as a penetration enhancer. The nanoemulsions were prepared by using the Microfluidizer. The oil phase consists of 10% w/w soybean oil and 5% w/w surfactant(s). Type of nanoemulsions was confirmed by dilution test. The average droplet size and size distribution (PDI) were measured by dynamic light scattering Zetasizer Nano ZS™. The …

Development Of Reimbursement Policy For Knee Osteoarthritis Treatment In Thailand, Parnnaphat Luksameesate

Chulalongkorn University Theses and Dissertations (Chula ETD)

Purpose : Osteoarthritis (OA) is the most common type of joint disease. The treatments are included oral non-steroidal anti-inflammatory drugs (NSAIDs), Symptomatic Slow-Acting Drugs for Osteoarthritis (SYSADOA), intra-articular steroid injection, and surgery. Each of treatments was a difference in benefit and risk. In addition to variation of reimbursement policy among three health insurance schemes in Thailand. The objective of this study was 1.) to conduct an economic evaluation of knee OA treatments in Thailand 2.) to investigate Thai patients’ preferences and their willingness-to-pay (WTPs) for knee OA treatments. Methods : A cost-utility analysis was conducted to compare among treatment options …

Variability In Antibacterial Activity In The Caribbean Sponge Amphimedon Compressa, Mackenzie Reilly

Honors Theses

Coral reefs are essential ecosystems that provide an abundance of natural resources. Sponges, common reef inhabitants, produce a diversity of secondary metabolites that are known to serve as chemical defenses. Secondary metabolites often have ecological functions, such as antipredator and antibacterial activities. I studied the common Caribbean sponge species, Amphimedon compressa, which is known to be chemically defended. Samples were collected from three sites in Belize, two sites in Grand Cayman, and three sites in St. Croix, U.S. Virgin Islands. To determine whether antibacterial activity varied across broad or local geographic scales, sponge extracts were tested against four bacterial strains …

The Interplay Of Progestins, Matrix Metalloproteinases, And The Aging Brain, Keyana Nicole Porter

Graduate Theses, Dissertations, and Problem Reports (ETD)

Progestins are synthetic hormones that are designed to mimic the biological actions of progesterone. They, however, possess other pharmacological actions and properties, in addition to their progestational activities. Medroxyprogesterone Acetate (MPA) is a progestin used globally in the hormonal contraceptive, Depo Provera®, by women in their reproductive prime and is a major compound found in hormone therapy (HT) formulations used by menopausal women. MPA is used by approximately 1 in 5 adolescents and adult women in the United States who are sexually active. Globally, nearly 48 million women utilize injectable contraceptives to prevent pregnancy, with most users utilizing MPA as …

Evaluation Of Rational Drug Use Project, Under The Support Of National Health Security Office, On Drug Utilization And Drug Management In Community Care Clinics In Bangkok, Dararat Samretwit

Chulalongkorn University Theses and Dissertations (Chula ETD)

Background: "The Network of Rational Drug Use Clinic (RDU Clinic)" campaign implemented in August 2015 to promote rational drug use in community caring clinic operated under National Health Security Office (NHSO) in Bangkok. The intervention composed of various measures such as education, managerial intervention, regulatory, and financial incentive. The purpose of the project is to evaluate and monitor the program effectiveness. Objectives: The purpose of the study is to evaluate the impact of RDU project on the quality of drug use in community care clinics in Bangkok using an interrupted time-series intervention analysis Methods: Quasi-experimental study using interrupted time series …

อิทธิพลของระดับความอิ่มตัวของทรานส์เฟอร์รินต่อดัชนีการดื้อยาอีริโทรโพอิตินในผู้ป่วยโรคไตเรื้อรังระยะที่ 4-5, อิ่มจิต บุญอำนวย

Chulalongkorn University Theses and Dissertations (Chula ETD)

วัตถุประสงค์: เพื่อศึกษาความสัมพันธ์ของระดับความอิ่มตัวทรานส์เฟอร์ริน (TSAT) กับดัชนีการดื้อยาอีริโทรโพอิติน (ERI) ในผู้ป่วยโรคไตเรื้อรังระยะที่ 4-5 วิธีการวิจัย: ในการศึกษาเชิงวิเคราะห์จากเหตุไปหาผลแบบย้อนหลังนี้ ผู้ป่วยโรคไตเรื้อรังระยะที่ 4-5 ที่ได้รับยาอีริโทรโพอิตินและมีการตรวจวัด TSAT ที่โรงพยาบาลบุรีรัมย์ ในช่วง ม.ค. 2560 ถึง ธ.ค. 2562 ถูกแบ่งออกเป็น 2 กลุ่มด้วยค่ามัธยฐานของระดับ TSAT (median TSAT) เพื่อเปรียบเทียบค่า ERI ที่คำนวณมาจากขนาดยาอีริโทรโพอิตินที่ใช้ต่อน้ำหนักตัวต่อสัปดาห์ (IU/kg/week) หารด้วยระดับฮีโมโกลบิน (g/dl) ระหว่างผู้ป่วย 2 กลุ่ม ผลการวิจัย: ผู้ป่วย 502 คนที่เข้าร่วมในการศึกษา มีค่ามัธยฐานของ TSAT เท่ากับร้อยละ 26.0 [IQR: ร้อยละ 17.9, ร้อยละ 36.0] และมัธยฐานของ ERI เท่ากับ 16.42 [IQR: 11.26, 21.25] IU/kg/week per g/dl มีผู้ป่วยในกลุ่มที่มี TSAT สูงกว่าค่ามัธยฐาน (>median TSAT) 246 คน และกลุ่ม TSAT ต่ำกว่าหรือเท่ากับค่ามัธยฐาน (≤median TSAT) 256 คน พบว่า ค่า ERI ในผู้ป่วยกลุ่ม >median TSAT ต่ำกว่ากลุ่ม ≤median TSAT อย่างมีนัยสำคัญทางสถิติ (15.04 [IQR: 9.74, 20.25] เทียบกับ 17.06 [IQR: 12.12, 22.50] IU/kg/week per g/dl ตามลำดับ, P= 0.003) สรุปผลการวิจัย: ผู้ป่วยโรคไตเรื้อรังระยะที่ …

เภสัชจลนศาสตร์ประชากรของยาเมอโรพีเนมในผู้ป่วยทารกขั้นวิกฤต, วัลย์ลิกา ยนต์วิเศษ

Chulalongkorn University Theses and Dissertations (Chula ETD)

วัตถุประสงค์: เพื่อวิเคราะห์หาค่าพารามิเตอร์และปัจจัยที่มีผลต่อค่าพารามิเตอร์ทางเภสัชจลนศาสตร์ของยาเมอโรพีเนมในผู้ป่วยเด็กทารกขั้นวิกฤต วิธีดำเนินการศึกษา: การศึกษาเชิงวิเคราะห์แบบเก็บข้อมูลไปข้างหน้า ในผู้ป่วยเด็กทารกขั้นวิกฤตอายุ 1 เดือน ถึง 2 ปี ที่ได้รับยาเมอโรพีเนมในการรักษา ณ โรงพยาบาลจุฬาลงกรณ์ สภากาชาดไทย ระหว่างวันที่ 4 กุมภาพันธ์ พ.ศ. 2563 ถึง 4 กุมภาพันธ์ พ.ศ. 2564 จำนวน 35 ราย ข้อมูลระดับยาในรูปอิสระของเมอโรพีเนมในเลือด จำนวน 160 ตัวอย่าง ถูกวิเคราะห์ด้วยเครื่อง high-performance liquid chromatography with ultraviolet (HPLC-UV) และนำมาสร้างแบบจำลองทางเภสัชจลนศาสตร์ประชากรโดยใช้โปรแกรม nonlinear mixed-effects modeling (NONMEM) ทดสอบความถูกต้องของแบบจำลองโดยการทดสอบภายในด้วยวิธี bootstrap analysis และวิเคราะห์กราฟ prediction-corrected visual predictive check (pcVPC) เพื่อประเมินความถูกต้อง แม่นยำในการทำนายของแบบจำลองสุดท้าย ผลการศึกษา: แบบจำลองทางเภสัชจลนศาสตร์แบบ one-compartment model with first-order elimination มีความเหมาะสมกับการศึกษานี้ อัตราการกำจัดยาและปริมาตรการกระจายยาของประชากรมีค่าเท่ากับ 1.33 ลิตรต่อชั่วโมง และ 2.27 ลิตร ตามลำดับ ปัจจัยที่มีผลต่ออัตราการกำจัดของยาเมอโรพีเนม คือ น้ำหนัก และอัตราการกำจัดของครีเอตินิน ส่วนปัจจัยที่มีผลต่อปริมาตรการกระจายของยาเมอโรพีเนม คือ น้ำหนัก ค่าความผันแปรระหว่างบุคคลของอัตรากำจัดยาและปริมาตรการกระจายยาเปรียบเทียบระหว่างแบบจำลองพื้นฐานและแบบจำลองสุดท้าย พบว่า มีค่าลดลงอย่างมีนัยสำคัญทางสถิติ ผลการประเมินแบบจำลอง พบว่า แบบจำลองสุดท้ายมีความถูกต้อง แม่นยำ และสามารถนำมาทำนายได้ดี สรุปผลการศึกษา: การศึกษานี้ได้พัฒนาและทดสอบความถูกต้องของแบบจำลองทางเภสัชจลนศาสตร์ประชากรของยาเมอโรพีเนมในผู้ป่วยเด็กทารกขั้นวิกฤต โดยพบว่า น้ำหนัก และอัตราการกำจัดของครีเอตินิน เป็นปัจจัยร่วมที่มีผลต่อค่าพารามิเตอร์ทางเภสัชจลนศาตร์ของยาเมอโรพีเนมอย่างมีนัยสำคัญทางสถิติ แบบจำลองทางเภสัชจลนศาสตร์ประชากรที่ได้จากการศึกษานี้สามารถนำมาเป็นแนวทางในการปรับขนาดยาเมอโรพีเนมให้เหมาะสมกับผู้ป่วยแต่ละรายในกลุ่มประชากรผู้ป่วยเด็กทารกขั้นวิกฤตที่มีลักษณะประชากรใกล้เคียงกับการศึกษานี้

Efficacy Of Cpap Compared To Standard Pharmacotherapy In Reducing Cognitive Impairment Symptoms In Patients With Alzheimer's Disease, Nicholas Moylan

Capstone Showcase

This review analyzed the following question: In adults age 65 years old or older diagnosed with Alzheimer’s Disease (P), is nightly use of CPAP (I) more effective in reducing cognitive impairment symptoms (O) than standard pharmacotherapy options (C)? A literature search conducted through Google Scholar and PubMed granted six relevant articles that provided data for this review. No current studies compared CPAP treatment with pharmacotherapy, and each study used unique measures of cognitive function, making direct comparison of the two therapies difficult. Results demonstrated that first line pharmacotherapy can improve cognitive function, but only in limited way and only in …

Oral Contraceptives As Possible Acl Injury Prevention Method, Haley Schweizer

Capstone Showcase

ABSTRACT

Introduction: Anterior Cruciate Ligament (ACL) injuries are an upsetting setback for many athletes that require a long and costly recovery process. The injury rates are four times greater in women than men. Preventative measures that help to prevent ACL injuries are limited to stretching and strengthening. Therefore, this review aims to investigate if oral contraceptive [I] usage provides a possible new avenue for prevention of ACL injury [O] in young female athletes (ages 18-30) [P] compared to those that do not take oral contraceptives [C].

Methods: A literature review was performed though PubMed, Google Scholar, SCOPUS Database, and ClinicalKey …

Community Pharmacists’ And Residents’ Decision Making And Unmet Information Needs When Completing Comprehensive Medication Reviews, Kacie L. Mcpherson, Omolola A. Adeoye-Olatunde, Jayna M. Osborne, William R. Doucette, Stephanie A. Gernant, Heather Jaynes, Shobha Phansalkar, Alissa L. Russ-Jara, Margie E. Snyder

Department of Pharmacy Practice Faculty Publications

Objective

To (1) characterize community pharmacists’ and community pharmacy residents’ decision making and unmet information needs when conducting comprehensive medication reviews (CMRs) as part of medication therapy management and (2) explore any differences between community pharmacists and community pharmacy residents in CMR decision making and unmet information needs.

Design

Thirty-to 60-minute semistructured interviews framed using a clinical decision-making model (CDMM) were conducted with community pharmacists and residents.

Setting and participants

Participants were recruited from practice-based research networks and researchers’ professional networks. Eligible participants had completed or supported the completion of at least 2 CMRs in the last 30 days.

Outcome …

Asthma-Copd Overlap: Economic Burden And Medication Adherence, Mona Nili

Graduate Theses, Dissertations, and Problem Reports (ETD)

In many older adults, asthma and chronic obstructive pulmonary disease (COPD) coexist as “Asthma-COPD overlap” (ACO). This dissertation pursued three Aims: 1) estimate the economic burden of ACO and its contributory factors; 2) evaluate the association of ACO to “cost-related medication nonadherence” (CRN); and 3) identify adherence trajectory patterns and examine the impact of initial maintenance therapies (IMT) type (inhaled corticosteroids monotherapy (ICS) vs. fixed-dose combination of ICS and long-acting beta agonist (ICS/LABA)) on adherence trajectory patterns among older adults Medicare Beneficiaries. The first and second Aims were cross-sectional studies by using Medicare Current Beneficiary Survey data. For the third …

Eecp Improves Markers Of Functional Capacity Regardless Of Underlying Ranolazine Therapy, Sanaz Ziad, Jamil Malik, Obinna Isiguzo, Lang Xu, Leqi Chen, Annette Cox, Sachin Shah

School of Pharmacy Faculty Articles

OBJECTIVE: Enhanced external counterpulsation (EECP) and ranolazine are approved treatments for patients with chronic stable angina by the United States Food and Drug Administration (FDA). Whether EECP offers clinical benefits regardless of underlying ranolazine therapy needs further investigation.

METHODS: This was a retrospective evaluation of patients referred to a specialized EECP center. Patients having data on 6-Minute Walk Distance (6MWD) or Duke Activity Status Index (DASI) were categorized into two groups (EECP with ranolazine or EECP only). The primary endpoints were change in 6MWD and DASI before and after a full course of EECP within each of the two groups. …

Modulation Of K V 7 Channel Deactivation By Pi(4,5)P 2, Carlos A. Villalba-Galea

School of Pharmacy Faculty Articles

The activity of K_V7 channels critically contributes to the regulation of cellular electrical excitability in many cell types. In the central nervous system, the heteromeric K_V7.2/K_V7.3 channel is thought to be the chief molecular entity giving rise to M-currents. These K⁺-currents as so called because they are inhibited by the activation of Gq protein-coupled muscarinic receptors. In general, activation of Gq protein-coupled receptors (GqPCRs) decreases the concentration of the phosphoinositide PI(4,5)P₂ which is required for K_V7 channel activity. It has been recently reported that the deactivation rate of K …

Enhancing Chemosensitivity Of Lung Cancers By Manipulating The Tumor Microenvironment: Local Lung Delivery And Nanocarrier-Based Therapies, Hanming Zhang

Theses and Dissertations

Cancer is the second leading cause of death in United States causing an estimated six hundred thousand death in 2019. Among different types of cancer, lung cancer is the leading cause of cancer related death in both male and female. While targeted therapy and immunotherapy have shown promising clinical outcomes, currently there remain a significant proportion of patients who do not benefit from these strategies or who cannot tolerate them, making Pt based doublet chemotherapy still an indispensable component in almost all stages of treatment. However, partially due to the poor tumor distribution of small molecule drug, the development of …

Interprofessional Peer Teaching: Assistive Device Training And Medications Impacting Safe Ambulation, Niamh M. Tunney, Melissa Chesson, Gina J. Ryan

Internet Journal of Allied Health Sciences and Practice

ABSTRACT

Purpose: An interprofessional peer teaching activity was designed and implemented to provide students with an opportunity to practice interprofessional education collaborative (IPEC) competencies while improving student knowledge of assistive devices for gait and medications impacting safe ambulation. Method: During the activity, second year physical therapy students instructed third year pharmacy students in the accurate fit and counseling for use of canes, crutches, and walkers. Pharmacy students then demonstrated these skills and were checked off on their ability to accurately fit and instruct consumers on basic gait patterns. The pharmacy students in turn educated the physical therapy students about medications …

A Case Of Intertrochanteric Fracture, Sahil Munjal

Digital Journal of Clinical Medicine

No abstract provided.

A Case Of Alcohol Induced Psychotic Disorder With Depression Presenting During Covid19 Lockdown, Dr. Sopan T, Dr Kishor M

Digital Journal of Clinical Medicine

No abstract provided.

A Case Of Spina Bifida Occulta With Tethered Cord Syndrome, Dr. Shivangi G, Dr. M.D. Ravi

Digital Journal of Clinical Medicine

No abstract provided.

A Case Of Squamous Cell Carcinoma, Dr. Pranav Prabhu, Dr. Gurgi Mukthinath

Digital Journal of Clinical Medicine

No abstract provided.

The Effects Of Scheduling Acetaminophen And Methocarbamol Administration On Postoperative Opioid Use And Related Side Effects Among Cardiac Surgery Patients, Whitney Jamison

DNP Projects

The Effects of Scheduled Acetaminophen and Methocarbamol Administration on Postoperative Opioid Use and Related Side Effects Among Cardiac Surgery Patients

ABSTRACT

Purpose

Opioid therapy is commonly prescribed to combat surgical pain in hospitals across the United States and is associated with many negative side effects including dependence and nausea. The purpose of this study was to retrospectively examine the effects of scheduling acetaminophen and methocarbamol administration postoperatively throughout the cardiac surgery patients’ hospital stay. Through retrospective chart reviews, the aims of postoperative opioid use, postoperative opioid use according to hospital length of stay, antiemetic use, and opioid prescription at discharge …

Using Electrolyte Repletion Guidelines To Improve The Rate Of Oral Potassium And Magnesium Delivery, Joshua Riley, Alan Kubey, Md

Phase 1

Introduction: Evidence-based guidelines for electrolyte replacement that safely encourage oral (PO) and/or intravenous (IV) dosing more successfully attain goal levels than standard care. However, the Thomas Jefferson University Hospital (TJUH) electrolyte replacement guidelines (JG 11-1296), approved in 2002 and last updated in 2008, provide guidance for IV repletion not PO. Between 5/2017-11/2017, TJUH dosed potassium and magnesium in a 2.30 and 4.24 IV:PO ratio, respectively. If 50% of doses were given PO, we anticipate ~$800,000 annual TJUH savings.

Methods: We created a multidisciplinary team and completed a literature review to inform the creation of updated TJUH guidelines for …

Antioxidant And Antimicrobial Activities Of Crude Extracts Of Actinomycetes From Soils, Khaing Zar Wai

Chulalongkorn University Theses and Dissertations (Chula ETD)

A total of 17 actinomycetes isolated from soil collected from Nong Khai, Nakhon Ratchasima, Khon Kaen, Phichit, Chachoengsao and Udonthani Province, were evaluated on antimicrobial and antioxidant activities. They were identified as Streptomyces (16 strains) and Micromonospora (1 strain) based on their phenotypic and chemotaxonomic characteristics including 16S rRNA gene sequences analysis. Strain JA03 showed 98.95% similarity of 16S rRNA gene sequence to S. puniciscabiei DSM 41929T. Strain JA03 was found to be the novel species of genus Streptomyces based on whole genome average nucleotide identity (ANI). All these strains were evaluated on antimicrobial and antioxidant activities. Based on agar …

Effect Of Jorunnamycin A On Cancer Stem Cells Of Human Lung Cancer H460 Cells, Somruethai Sumkhemthong

Chulalongkorn University Theses and Dissertations (Chula ETD)

It has been recognized that cancer stem-like cells (CSCs) in tumor tissue crucially contribute to therapeutic failure, resulting in a high mortality rate in lung cancer patients. Due to their stem-like features of self-renewal and tumor formation, CSCs can lead to drug resistance and tumor recurrence. Herein, the suppressive effect of jorunnamycin A, a bistetrahydroisoquinolinequinone isolated from Thai blue sponge Xestospongia sp., on cancer spheroid initiation and self-renewal in the CSCs of human lung cancer cells is revealed. The depletion of stemness transcription factors, including Nanog, Oct-4, and Sox2 in the lung CSC-enriched population treated with jorunnamycin A (0.5 µM), …

Aloe Vera And Health Outcomes: An Umbrella Review Of Systematic Reviews And Meta-Analyses, Saranrat Sadoyu

Chulalongkorn University Theses and Dissertations (Chula ETD)

This umbrella review aims to summarize and assess the effects of Aloe vera on health outcomes. Methods: Only systematic reviews and meta-analyses of clinical trials that investigated the effects of Aloe vera on health outcomes were eligible. PubMed, Scopus, Embase, Cochrane database of systematic reviews, CINAHL, and AMED were searched from inception to October 2019. Two independent reviewers extracted data, assessed the methodological quality, and rated the credibility of evidence according to established criteria into convincing, highly suggestive, suggestive, weak, and not significant. Results: Ten articles reporting 71 unique outcomes of Aloe vera were included. Of these, 47 (67%) were …

Production Of Recombinant Protein Ltb-Ctla4 By Transient Plant-Based Expression Using Geminiviral Vector, Sutita Yiemchavee

Chulalongkorn University Theses and Dissertations (Chula ETD)

Cancer is one of the leading global causes of death. In 2018, WHO estimated that 9.6 million patients died from cancer, with 18.1 million new cases emerged. In recent years, immunotherapy is considered as a treatment improving cancer-related immune function by manipulating the immune checkpoints in the immune system. Cytotoxic-T-lymphocyte antigen 4 (CTLA-4) is a immune checkpoint transmembrane protein. The expression of CTLA-4 on the surface of activated T-cell could downregulate the production and proliferation of cytotoxic T-lymphocyte cells (CTLs). CTLs are the host-defended immune cells that could retard the growth of cancer cells by recognizing the tumor-associated antigens expressed …

Formulation Development Of Extended And Immediate Release Tablets Using Extrusion-Based 3d Printing Technology, Yee Mon Than

Chulalongkorn University Theses and Dissertations (Chula ETD)

Fused deposition modelling (FDM) based 3D printing technology for oral solid dosage form has shown promising results in the fabrication of individualized tablets compared to conventional method. However, the main concern of this technique is the quality of drug loaded filament including mechanical properties such as flexibility, stiffness and brittleness. To cope with these problems, filaments were produced via hot melt extrusion (HME) by screening and characterizing a series of pharmaceutical mixtures (6 types of polymers and 5 types of disintegrants) and processing parameters for specifying the design space in Design of Experiment (DoE). Therefore, the purposes of the present …

Multicellular Spheroids Of A549 And A549-Irfp As An In Vitro Model Of Lung Cancer, Xinyu Pei

University of the Pacific Theses and Dissertations

Lung cancer is the second most common cancer in both men and women around the world, and 85% of it is non-small cell lung cancer (NSCLC). It is estimated that in 2020, there will be 228,820 cases of lung cancer and 135,720 deaths from lung (American Cancer Society, 2020). The prognosis of lung cancer is poor (

Traditionally, the most commonly used in vitro method for screening therapeutic drugs is monolayer cell cultures, which are reproducible, convenient and of low cost. However, monolayer cell culture models are unable to reproduce many properties of in vivo solid tumors such as the …

Tubular Adenoma Of Breast, Diksha Dadlani

Digital Journal of Clinical Medicine

No abstract provided.