Fabry Disease From a Patient’s Perspective, Featuring Maya Kineen

This continuing education activity is provided by AffinityCE and CheckRare CE. This activity provides continuing education credit for physicians. A statement of participation is available for other attendees. Estimated time to complete: 0.50 hoursTo obtain CME credit, go to https://checkrare.com/learning/p-cushings-syndrome-treatment-research-highlights-endo-2024/Commercial SupportEducational Support for this activity was provided by Recordati Rare Diseases, Inc., and Xeris Pharmaceuticals.Learning ObjectiveAfter participating in the activity, learners should be better able to:Describe the latest research being presented to better manage individuals with Cushing’s syndrome and its clinical relevance.Share new information with their clinical team. Activity DescriptionThis 30-minute CME program highlights the latest clinical research about Cushing’s syndrome and Cushing’ disease.Cushing’s syndrome is rare endocrine disorder characterized by chronic hypercortisolism. It is often due to a pituitary adenoma producing excessive ACTH leading to hypercortisolism. Symptoms can range from mild to extensive.This CME program, hosted by Maria Fleseriu, MD, FACE, Professor of Medicine and Neurological Surgery, Director of the Pituitary Center at Oregon Health & Science University, provides an overview of the latest clinical research presented at ENDO 20234 involving Cushing’s syndrome. FacultyMaria Fleseriu, MD, FACEProfessor of Medicine and Neurological SurgeryDirector of Pituitary CenterOregon Health & Science UniversityPortland, OregonDisclosure StatementAffinityCE and CheckRare CE staff, as well as planning and review committees, have no financial interests to disclose. Faculty EducatorsDr. Fleseriu discloses the following relevant financial relationships with ineligible companies to disclose:Funding to the University as Principle Investigator from Sparrow PharmaceuticalsScientific consultant for Crinetics Pharmaceuticals, Recordati Rare Diseases, Sparrow Pharmaceuticals, and Xeris PharmaceuticalsMitigation of Relevant Financial Relationships AffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible companies. Method of ParticipationThere are no fees to participate in the activity. Participants must review the activity information including the learning objectives and disclosure statements, as well as the content of the activity. To receive CME credit for your participation, please complete the pre- and post-program assessments. Your certificate will be emailed to you in within 30 days.Participation CostsThere is no cost to participate in this CME session. To receive CME credit for your participation, please complete the pre- and post-program assessments. Your certificate will be emailed to you in within 30 days.CME InquiriesFor all CME policy-related inquiries, please contact us at [email protected] customer support requests to [email protected]© 2024. This CME-certified activity is held as copyrighted © by AffinityCE and CheckRare CE. Through this notice, AffinityCE and CheckRare CE grant permission of its use for educational purposes only. These materials may not be used, in whole or in part, for any commercial purposes without prior permission in writing from the copyright owner(s). 

Yuliya Linhares, MD is a medical oncologist specializing in the comprehensive treatment of lymphoma and serves as chief of Lymphoma Services at Miami Cancer Institute. In this video, Dr. Linhares provides an overview of cutaneous T-cell lymphoma (CTCL) and discusses some strategies for shortening the diagnostic journey of this rare cancer.The diagnosis of CTCL is often challenging; as a result, delays in diagnosis (and subsequent work-up and treatment) can be significant. Part of the reason is the variability in how individual patients present with CTCL and its subtypes. Because mycosis fungoides progresses slowly, some patients may not experience progression beyond their initial symptoms, even beyond 10 years. Patients with mycosis fungoides or Sézary syndrome also have overlap in manifestations; in fact, Sézary syndrome was once classified as a malignant, leukemic variant of mycosis fungoides but is now recognized as a distinct CTCL subtype.Patients with mycosis fungoides may progress through three phases of skin symptoms. The first may feature little more than transient red, scaly areas of skin on the buttocks and torso. The plaques may be hyper- or hypopigmented. As such, these symptoms can be easily misidentified as common skin conditions such as eczema or psoriasis. The variability of signs and symptoms also adds to the challenge of making a timely, clear-cut diagnosis.In the second phase, patients with progressing disease may develop palpable, scaly, reddish-brown plaques that appear on any portion of the body. Over time, the affected areas of skin may grow, merging with other affected regions. Patients’ skin presentation during this stage can vary considerably: Some patients may experience severe pruritus or pain in these scaly bumps, which can result in sleep disturbances and other challenges to quality of life. Other patients may remain asymptomatic other than the skin’s appearance.Disease presentation is a bit more consistent in patients who have progressed to the third phase of skin symptoms. Some patients may develop mushroom-shaped skin tumors that can cause skin ulceration and infection. Even for patients with mycosis fungoides reaching this phase of skin progression, malignant spread is uncommon (only 10% will experience metastases to major organs).While patients with Stage III mycosis fungoides experience widespread erythema (over 80% of body surface area), erythroderma is a consistent feature of Sézary syndrome. This rash will often be associated with severe pruritus and peeling.In addition to erythroderma and B2 blood involvement, patients with Sézary syndrome will typically have several other characteristic signs: generalized lymphadenopathy, opportunistic infections, and alopecia. The liver and possibly the spleen will be enlarged, and patients often have very thick, coarse skin on the soles of the feet and palms of the hands (i.e., palmoplantar keratoderma).Diagnosis is usually made with a patient history, complete physical exam, blood tests, biopsy of skin lesions, computed tomography imaging, and sometimes lymph node biopsy and/or bone marrow biopsy. These methods can also be useful in determining the stage of disease, especially whether the lymph nodes have been involved and whether the cancerous cells have spread to blood and other organs. In addition to eczema and psoriasis, the differential diagnosis may include nonspecific dermatitis, lichen, lupus, pseudolymphoma, parapsoriasis, and toxidermia.To learn more about CTCL, visit our Cutaneous T-Cell Lymphoma (CTCL) Learning Center page. https://checkrare.com/cutaneous-t-cell-lymphoma-2/

Larisa Geskin, MD, Professor of Dermatology at Columbia University Medical Center and Director of the Comprehensive Skin Cancer Center at the Division of Cutaneous Oncology in the Department of Dermatology, discusses the challenges of diagnosing cutaneous T-cell lymphoma (CTCL).The diagnosis of CTCL is often challenging; as a result, delays in diagnosis (and subsequently work-up and treatment) can be significant. Part of the reason is the variability in how individual patients present with CTCL and its subtypes. Because mycosis fungoides progresses slowly, some patients may not experience progression beyond their initial symptoms, even beyond 10 years. Patients with mycosis fungoides or Sézary syndrome also have overlap in manifestations; in fact, Sézary syndrome was once classified as a malignant, leukemic variant of mycosis fungoides but is now recognized as a distinct CTCL subtype.Patients with mycosis fungoides may progress through three phases of skin symptoms. The first may feature little more than transient red, scaly areas of skin on the buttocks and torso. The plaques may be hyper- or hypopigmented. As such, these symptoms can be easily misidentified as common skin conditions such as eczema or psoriasis. The variability of signs and symptoms also adds to the challenge of making a timely, clear-cut diagnosis.In the second phase, patients with progressing disease may develop palpable, scaly, reddish-brown plaques that appear on any portion of the body. Over time, the affected areas of skin may grow, merging with other affected regions. Patients’ skin presentation during this stage can vary considerably: Some patients may experience severe pruritus or pain in these scaly bumps, which can result in sleep disturbances and other challenges to quality of life. Other patients may remain asymptomatic other than the skin’s appearance.Disease presentation is a bit more consistent in patients who have progressed to the third phase of skin symptoms. Some patients may develop mushroom-shaped skin tumors that can cause skin ulceration and infection. Even for patients with mycosis fungoides reaching this phase of skin progression, malignant spread is uncommon (only 10% will experience metastases to major organs).While patients with Stage III mycosis fungoides experience widespread erythema (over 80% of body surface area), erythroderma is a consistent feature of Sézary syndrome. This rash will often be associated with severe pruritus and peeling.In addition to erythroderma and B2 blood involvement, patients with Sézary syndrome will typically have several other characteristic signs: generalized lymphadenopathy, opportunistic infections, and alopecia. The liver and possibly the spleen will be enlarged, and patients often have very thick, coarse skin on the soles of the feet and palms of the hands (i.e., palmoplantar keratoderma).Diagnosis is usually made with a patient history, complete physical exam, blood tests, biopsy of skin lesions, computed tomography imaging, and sometimes lymph node biopsy and/or bone marrow biopsy. These methods can also be useful in determining the stage of disease, especially whether the lymph nodes have been involved and whether the cancerous cells have spread to blood and other organs. In addition to eczema and psoriasis, the differential diagnosis may include nonspecific dermatitis, lichen, lupus, pseudolymphoma, parapsoriasis, and toxidermia.To learn more about CTCL, visit our Cutaneous T-Cell Lymphoma (CTCL) Learning Center page. https://checkrare.com/ctcl-the-role-of-dermatologists-in-diagnosing-and-caring-for-patients/

Jointly Provided by American Academy of CME and CheckRare CE.Supported by educational grants from argenx US, Inc. and UCB Inc.To claim credit for this program, please visit https://checkrare.com/learning/p-myasthenia-gravis-research-highlights-aan-2024/Estimated time to complete: 0.5 hoursStart date: June 15, 2024End date: June 30,2025Activity DescriptionThis accredited CME program highlights the latest clinical research about myasthenia gravis, a rare, autoimmune disease that targets the neuromuscular junction.Treatment of myastheniagravis is highly individualized and depends greatly on the myasthenia gravis subtype of each patient as well as each patient’s comorbidities. There are currently five drugs approved by the FDA, eculizumab, efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan. Clinical trial data on these therapies, as well as real world data, were presented at the American Academy of Neurology Annual Meeting (AAN 2024) held in Denver, CO.This CME activity, hosted by Nicholas Silvestri, MD, of the University of Buffalo, provides an overview of the latest clinical research presented at AAN 2024 focused on myasthenia gravis.Activity FacultyNicholas Silvestri, MDProfessor of NeurologyUniversity of Buffalo Jacobs School of Medicine and Biomedical SciencesTarget AudienceThis activity has been designed to meet the educational needs of physicians specializing in neurology, ophthalmology, and general practice. Other members of the care team may also participate.Learning ObjectiveAfter participating in the activity, learners should be better able to:Describe the latest research being presented to better manage people with myasthenia gravis and its clinical relevanceAccreditation and Credit DesignationIn support of improving patient care, this activity has been planned and implemented by American Academy of CME, Inc. and CheckRare CE. American Academy of CME, Inc. is Jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.PhysiciansAmerican Academy of CME, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure StatementAccording to the disclosure policy of the Academy, all faculty, planning committee members, editors, managers and other individuals who are in a position to control content are required to disclose any relationships with any ineligible company(ies). The existence of these relationships is not viewed as implying bias or decreasing the value of the activity. Clinical content has been reviewed for fair balance and scientific objectivity, and all of the relevant financial relationships listed for these individuals have been mitigated.Disclosure of relevant financial relationships are as follows:Faculty EducatorDr. Silvestri discloses the following relevant financial relationships with ineligible companies:Advisory Board/Consultant: argenx, Alexion, UCB, Immunovant, Janssen, AmgenSpeakers Bureau: argenx, Alexion, UCB, TakedaPlanners for this activity have no relevant financial relationships with any ineligible companies.This activity will review off-label or investigational information. The opinions expressed in this educational activity are those of the faculty, and do not represent those of the Academy or CheckRare CE. This activity is intended as a supplement to existing knowledge, published information, and practice guidelines. Learners should appraise the information presented critically, and draw conclusions only after careful consideration of all available scientific information.Method of ParticipationThere are no fees to participate in the activity.  Participants must review the activity information including the learning objectives and disclosure statements, as well as the content of the activity. To receive CME credit for your participation, please complete the pre and post-program assessments. Your certificate will be emailed to you in within 30 days.PrivacyFor more information about the American Academy of CME privacy policy, please access http://www.academycme.org/privacy.htm  For more information about CheckRare’s privacy policy, please access https://checkrare.com/privacy/ContactFor any questions, please contact: [email protected]© 2024. American Academy of CME and CheckRare CE. These materials may not be used, in whole or in part, for any commercial purposes without prior permission in writing from the copyright owner(s). 

In this episode of our series focused on Fabry disease, we feature Maya Kineen, a patient and advocate with this rare disorder.Fabry disease is an inherited disorder that results from the buildup of a particular type of fat, called globotriaosylceramide, in the body's cells. Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity); problems with the gastrointestinal system; ringing in the ears (tinnitus); and hearing loss. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys.

This is the second of a three-part series focusing on Fabry disease. In this episode, we talk with Nicola Longo, MD, Chief of the Division of Medical Genetics at the University of Utah, Spencer Fox Eccles School of Medicine in Salt Lake City. Dr. Longo discusses Fabry disease, including the progression of the disease and personalized medicine.Fabry disease is an inherited disorder that results from the buildup of globotriaosylceramide or GL-3. The disorder affects many parts of the body. Signs and symptoms may include acroparesthesias, angiokeratomas, hypohidrosis, corneal opacity, and hearing loss. Potentially severe complications can include progressive kidney damage, heart attack, and stroke. Fabry disease is caused by mutations in the GLA gene and is inherited in an X-linked manner. Treatment may include enzyme replacement therapy (ERT); pain medications, ACE inhibitors; and chronic hemodialysis or renal transplantation for end stage renal disease.

In this first part of our four-part series on Fabry disease, we feature William Burns, MD, a biochemical geneticist at Greenwood Genetic Center in Greenwood, South Carolina. Dr. Burns summarizes this rare disease, including current management strategies.Fabry disease is a lysosomal storage disorder, meaning that a glycosphingolipid called GL-3 accumulates in the lysosomes, causing tissue damage; many cell types are affected.The disease is caused by mutations in the GLA gene, resulting in nonfunctional or dysfunctional alpha-galactosidase A, a lysosomal enzyme. The mutations can be inherited, so multiple family members can have the disease.Fabry disease is a multisystemic disease, affecting many organs, including the heart, kidney and nervous system, resulting in life-threatening complications and a reduced life expectancy. Early signs of the disease start in childhood and adolescence, but it is a progressive, lifelong condition.Newborn screening has now been performed in several countries, yielding a prevalence ranging from 1 in 1,368 to 1 in 8,882 births.

Ozlem Goker-Alpan, MD, Founder and President, LDRTC and David G. Warnock, MD. Professor of Medicine (Emeritus) at University of Alabama at Birmingham discuss best practices to identify and treat kidney problems associated with lysosomal disorders.This CME/CE activity describes the pathophysiologies and management options for lysosomal disease patients with kidney problems. This continuing education activity is provided through collaboration between the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC), CheckRare CE, and AffinityCE. This activity provides continuing education credit for physicians, physician assistants, nurses, nurse practitioners, and genetic counselors. A statement of participation is available to other attendees. To receive credit for this program, go to https://checkrare.com/learning/ Speakers Ozlem Goker-Alpan, MD, Founder and President, LDRTC David G. Warnock, MD. Professor of Medicine (Emeritus)University of Alabama at BirminghamDisclosuresAffinityCE staff, LDRTC staff, CheckRare staff, planners, and reviewers, have no relevant financial interests to disclose. All faculty disclosures are listed below and are included in the beginning of each presentation.Dr. Goker-Alpan is a consultant, a principal investigator and /or on the speaker bureau, or has received grant support, from the following pharmaceutical companies: Actelion, Amicus Therapeutics, Sanofi, Takeda, Pfizer/Protalix.Dr. Warnock has had research support and/or consulting arrangements with Genzyme Corporation (Sanofi), Shire LLC (Takeda), Amicus, Protalix and Chiesi, Zebra Bio, Walking Fish, Hanmi, and Vera Therapeutics.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity. Conflicts of interest for presenting faculty with relevant financial interests were resolved through peer review of content by a non-conflicted reviewer.Learning ObjectivesAt the end of this activity, participants should be able to:Describe the role of the nephrologist in the team approach to careDescribe best practices to monitor kidney function in lysosomal disordersDescribe best practices to treat kidney disorders lysosomal disordersSupport for this educational activity was provided by Takeda, Sanofi, Amicus Therapeutics and Chiesi USA.

This 16-minute CME-accredited program, hosted by Aleena Banerji, MD, Associate Professor at Harvard Medical School and Clinical Director of the Massachusetts General Hospital ( MGH) Allergy and Immunology Unit, highlights the future treatment options for patients with hereditary angioedema (HAE) presented at ACAAI 2023. Jointly Provided by American Academy of CME and CheckRare CE. Support for this accredited continuing education activity has been made possible through educational grant from Ionis Pharmaceuticals Inc. Estimated time to complete: 0.25 hours Start date: January 31, 2024 End date: January 30, 2025To obtain CME credit, go to https://checkrare.com/learning/p-hae-treatment-advances-highlights-from-acaai/Activity Faculty Aleena Banerji, MD Associate Professor Clinical Director, MGH Allergy and Immunology Unit Harvard Medical School Massachusetts General Hospital Boston, MA Target Audience This activity has been designed to meet the educational needs of physicians specializing in allergy medicine, immunology, internal medicine, and pediatrics who may be involved in the care for individuals with HAE. Other healthcare providers (HCPs) may also participate. Learning Objectives After participating in the activity, learners should be better able to • Understand clinical data of treatments in development for HAE Accreditation and Credit Designation In support of improving patient care, this activity has been planned and implemented by American Academy of CME, Inc. and CheckRare CE. American Academy of CME, Inc. is Jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physicians American Academy of CME, Inc., designates this enduring material for a maximum of 0.25 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Other HCPs Other members of the care team will receive a certificate of participation. Disclosure Statement According to the disclosure policy of the Academy, all faculty, planning committee members, editors, managers and other individuals who are in a position to control content are required to disclose any relationships with any ineligible company(ies). The existence of these relationships is not viewed as implying bias or decreasing the value of the activity. Clinical content has been reviewed for fair balance and scientific objectivity, and all of the relevant financial relationships listed for these individuals have been mitigated. Disclosure of relevant financial relationships are as follows: Faculty Educator Dr. Banerji discloses the following relevant financial relationships with ineligible companies: • Research Grant: Takeda, Ionis Pharmaceuticals, Astria • Advisory Board: Takeda, BioCryst, Astria, Intellia, CSL Behring, KalVista, ADARx Planners for this activity have no relevant financial relationships with any ineligible companies. This activity will review off-label or investigational information. The opinions expressed in this educational activity are those of the faculty, and do not represent those of the Academy or CheckRare CE. This activity is intended as a supplement to existing knowledge, published information, and practice guidelines. Learners should appraise the information presented critically, and draw conclusions only after careful consideration of all available scientific information. Method of Participation There are no fees to participate in the activity. Participants must review the activity information including the learning objectives and disclosure statements, as well as the content of the activity. To receive CME credit for your participation, please complete the pre and post-program assessments at https://checkrare.com/learning/p-hae-treatment-advances-highlights-from-acaai/ Your certificate will be emailed to you in within 30 days. Privacy For more information about the American Academy of CME privacy policy, please access http://www.academycme.org/privacy.htm For more information about CheckRare’s privacy policy, please access https://checkrare.com/privacy/ Contact For any questions, please contact: [email protected] Copyright © 2024. This CME-certified activity is held as copyrighted © by American Academy of CME and CheckRare CE. Through this notice, the Academy and CheckRare CE grant permission of its use for educational purposes only. These materials may not be used, in whole or in part, for any commercial purposes without prior permission in writing from the copyright owner(s).

This 25-minute CME-accredited program, hosted by Aleena Banerji, MD, Associate Professor at Harvard Medical School and Clinical Director of the Massachusetts General Hospital ( MGH) Allergy and Immunology Unit, highlights the current treatment options for patients with hereditary angioedema (HAE). Jointly Provided by American Academy of CME and CheckRare CE. Support for this accredited continuing education activity has been made possible through educational grant from Ionis Pharmaceuticals Inc. Estimated time to complete: 0.50 hours Start date: January 31, 2024 End date: January 30, 2025To obtain CME credit, go to https://checkrare.com/learning/p-hereditary-angioedema-current-treatment-options/Activity Faculty Aleena Banerji, MD Associate Professor Clinical Director, MGH Allergy and Immunology Unit Harvard Medical School Massachusetts General Hospital Boston, MA Target Audience This activity has been designed to meet the educational needs of physicians specializing in allergy medicine, immunology, internal medicine, and pediatrics who may be involved in the care for individuals with HAE. Other healthcare providers (HCPs) may also participate. Learning Objectives After participating in the activity, learners should be better able to • Review current guidelines and unmet needs of patients with HAE Accreditation and Credit Designation In support of improving patient care, this activity has been planned and implemented by American Academy of CME, Inc. and CheckRare CE. American Academy of CME, Inc. is Jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physicians American Academy of CME, Inc., designates this enduring material for a maximum of 0.50 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Other HCPs Other members of the care team will receive a certificate of participation. Disclosure Statement According to the disclosure policy of the Academy, all faculty, planning committee members, editors, managers and other individuals who are in a position to control content are required to disclose any relationships with any ineligible company(ies). The existence of these relationships is not viewed as implying bias or decreasing the value of the activity. Clinical content has been reviewed for fair balance and scientific objectivity, and all of the relevant financial relationships listed for these individuals have been mitigated. Disclosure of relevant financial relationships are as follows: Faculty Educator Dr. Banerji discloses the following relevant financial relationships with ineligible companies: • Research Grant: Takeda, Ionis Pharmaceuticals, Astria • Advisory Board: Takeda, BioCryst, Astria, Intellia, CSL Behring, KalVista, ADARx Planners for this activity have no relevant financial relationships with any ineligible companies. This activity will review off-label or investigational information. The opinions expressed in this educational activity are those of the faculty, and do not represent those of the Academy or CheckRare CE. This activity is intended as a supplement to existing knowledge, published information, and practice guidelines. Learners should appraise the information presented critically, and draw conclusions only after careful consideration of all available scientific information. Method of Participation There are no fees to participate in the activity. Participants must review the activity information including the learning objectives and disclosure statements, as well as the content of the activity. To receive CME credit for your participation, please complete the pre and post-program assessments at https://checkrare.com/learning/p-hereditary-angioedema-current-treatment-options/ Your certificate will be emailed to you in within 30 days. Privacy For more information about the American Academy of CME privacy policy, please access http://www.academycme.org/privacy.htm For more information about CheckRare’s privacy policy, please access https://checkrare.com/privacy/ Contact For any questions, please contact: [email protected] Copyright © 2024. This CME-certified activity is held as copyrighted © by American Academy of CME and CheckRare CE. Through this notice, the Academy and CheckRare CE grant permission of its use for educational purposes only. These materials may not be used, in whole or in part, for any commercial purposes without prior permission in writing from the copyright owner(s).