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To study the demographics, characteristics, management and disease outcome of Egyptian children with juvenile dermatomyositis (JDM).Retrospective analysis of the records of 134 JDM patients attending two centres in Cairo, Egypt from January 2010 to December 2019. A total of 128 patients were included in the study, all of which fulfilled either the Bohan and Peter criteria and/or the EULAR/ACR classification criteria of 2017.The mean age of disease onset was 5.9±2.8 years and the follow-up duration were 6±3.2 years. Female to male ratio was 2.2:1. Constitutional manifestations and cutaneous skin ulcers were common, while gut vasculopathy was rare in our patients. Heliotrope rash was the commonest skin manifestation. Lactate dehydrogenase enzyme was more frequently elevated than creatine kinase. Electromyography was the most frequently used diagnostic procedure, while muscle biopsy and muscle MRI were not commonly done in our patients. Glucocorticoids, methotrexate, hydroxychloroquine, mycophenolate mofetil and IVIG were the most frequently used medications. Sixty (46.9 %) of the patients had clinically inactive disease, at the last follow-up visit. Chronic skin disease, residual muscle weakness, calcinosis and growth failure were among the most common cumulative damage manifestations. The mortality rate was 1.6% over the follow-up period, one death was due to severe infection, and the other due to respiratory failure.Although our patients shared several similarities with their peers in the Middle East and in Europe, there were some striking differences. These differences can be attributed to the ethnic and environmental disparities.

Estimates of the global prevalence of rheumatoid arthritis (RA) range from 0.24 to 1%, but vary considerably around the globe. A variation in RA prevalence is also expected across Africa and the Middle East, due to ethnic, climate, and socioeconomic differences. To assess the prevalence of RA in Africa and the Middle East, we searched Medline (via PubMed) and databases of major rheumatology conferences. Seventeen journal articles and 0 abstracts met the inclusion criteria. Estimated prevalence ranged from 0.06 to 3.4%. Most studies reported values near or below 0.25%. Consistent with data from other regions, RA was more prevalent among urban than rural populations, and among women than men. The women:men prevalence ratio ranged from 1.3:1 to 12.5:1, which suggests notable differences from the global average of 2:1. Relative increases in prevalence were observed in North Africa and the Middle East (13% since 1990) and Western Sub-Saharan Africa (14%), whereas rates in Eastern, Central, and Southern Sub-Saharan Africa show decreases (4-12%). Low disease awareness, delays to visit rheumatologists, and socioeconomic factors appear to hinder early diagnosis and aggressive treatment. Few countries have developed RA-specific treatment guidelines, and many physicians and patients face limited access to even basic treatments. An improved understanding of the epidemiology and management of RA, and the related socioeconomic consequences is necessary, so that targeted attempts can be made to encourage early diagnosis and treatment.

Psoriatic arthritis (PsA) is a chronic, inflammatory arthropathy occurring in up to 30% of patients with psoriasis, and is characterized by multiple manifestations including peripheral arthritis, enthesitis, dactylitis, spondylitis, and psoriatic skin and nail disease. This complex and heterogeneous disease is poorly understood and its diagnosis and treatment are suboptimal, particularly in Africa and the Middle East, where very few studies into the impact of PsA have been carried out. This article aims to highlight the disease burden of PsA in the region as well as to identify unmet clinical needs. A non-systematic review was carried out in the PubMed database and the most relevant publications were selected. Expert rheumatologists practicing in Africa and the Middle East provide an insight into the challenges of treating PsA in daily practice, along with recommendations for improvements.

Aim of the work: To study patterns and disease subsets of Behcet’s disease (BD) patients admitted to Cairo University Hospitals and to detect whether relapse of the disease will affect the same system every time or not. Patients and methods: A retrospective study involving 82 BD patients admitted to Cairo University Hospitals, from January 2000 to December 2014. They were reviewed to analyze the frequency of different disease manifestations and to find out disease patterns and subsets. Results: 75 men and 7 women were included in the study, with a mean age of 34.2 ± 9.7 years. Their disease duration ranged from 1 to 34 years with a mean of 9.1 ± 6.9 years. Mucocutaneous manifestations were present in 82 patients (100%), ocular manifestations in 53 patients (64.4%), vascular manifestations in 49 patients (59.8%), and neurological manifestations in 9 patients (11%). Most of our patients, 48 (58.5%) had the same one system pattern throughout the disease course, 25 patients (30.5%) had two systems patterns and 9 patients (11%) had three systems patterns. Conclusion: BD usually affects the same system throughout the disease course whether mucocutaneous, vascular, ocular or neurological and the most common pattern is the one system affection. This will help to predict the system that will be affected in each time the patient presents with a disease relapse. Also, it will help in differentiation between disease relapse and any associated other disease minimizing the need for and the cost of investigations. However, future studies on larger number of patients are recommended. Keywords: Behcet's disease, Disease relapse, Disease patterns, Disease subsets

Introduction Disease features and laboratory abnormalities differ among adult-onset and childhood-onset systemic lupus erythematosus (aSLE and cSLE). Socioeconomic status both independent of, and in combination with, ethnicity influences the disease phenotype and outcome. Objective To compare the various disease features among patients with cSLE and aSLE in a limited monetary income Egyptian cohort attending a large free-of-charge university hospital. Patients and methods: Retrospective analysis of the medical records of 714 SLE patients attending Cairo University Hospitals from January 2000 to December 2019. Of them 602 (400 with aSLE and 202 with cSLE) were enrolled in the study. Results The mean age of disease onset was 28.27 ± 10.55 among aSLE patients compared to 12.88 ± 4.26 years among cSLE patients. Disease duration was 12.03 ± 5.05 and 4.14 ± 3.18 years in aSLE and cSLE, respectively. Female to male ratio was 15:1 among patients with aSLE, as compared to 2.67:1 among cSLE (Conclusion Arthritis was the most common clinical manifestation over time in aSLE compared to renal involvement in cSLE. Renal disease tends to be more active in cSLE. The differences in disease manifestations between this cohort and other studies can be attributed to the ethnic and socioeconomic disparities.

Aim of the work: Ocular manifestations are the main cause of morbidity in Behcet's disease (BD). Infliximab (IFX), a chimeric monoclonal antibody directed against tumor necrosis factor-alpha, may be efficient in refractory uveitis due to BD. The aim of this study was to assess the efficacy and safety of IFX in the treatment of patients with BD-associated refractory posterior uveitis (PU). Patient and Methods: Twenty patients with refractory Behcet's PU received IFX therapy as intravenous infusions at the dose of 5 mg/kg at weeks 0,2, 6 (induction) and every 8 weeks for a maximum of 6 infusions. Results: The mean age of the patients was 31.8 ± 9.1 years, disease duration was 8 ± 6 years and 17 (85%) were males. After the third IFX infusion (week 8) a complete remission of PU was recorded in 8/20 (40%) patients and partial remission in 12/20 (60%) patients. At the end of week 32 a complete remission of PU was recorded in a total of 14 (70%) patients. The visual acuity of the 36 affected eyes (16 bilateral and 4 unilateral) showed a significant improvement at the week 8, and at week 32, while there was no additional improvement at week 56. Relapse occurred in 6 patients (30%) between week 9 and week 18 with a mean of 13.5 weeks. Conclusion: IFX infusion should be considered for the control of acute PU, whereas repeated long-term IFX infusions were effective in reducing the number of episodes in refractory PU with fast regression and complete remission of complications. Keywords: Behçet’s disease, Posterior uveitis, Retinal vasculitis, Infliximab

Aim of the work: To study and analyze the clinical features of Egyptian systemic lupus erythematosus (SLE) patients with pleuro-pulmonary system involvement. Patients and methods: All SLE patients admitted to the Rheumatology and Rehabilitation inpatient Department, Cairo University Hospitals, during the period from the years 2000 to 2013 were reviewed. Medical records of the patients were revised and data from patients with any clinical, pathological and radiological findings confirming the presence of pleuropulmonary system affection were analyzed. Results: Pleuro-pulmonary involvement occurred in 265/402 (65.9%) patients. Pleurisy was the most common clinical finding in 163 (61.5%), pulmonary infection in 57.7% and pleural effusion in 24.5% cases. Less common manifestations were pulmonary hypertension (8.3%), interstitial lung fibrosis (4.2%) and diffuse alveolar haemorrhage (n = 8; 3%). The most common clinical symptoms were pleuritic chest pain (50.9%) and cough (49.1%). The most common auto-antibodies were antinuclear antibodies (ANA) (94.7%) and anti-dsDNA in 159/183 (86.8%) cases. In the present study, the muco-cutaneous manifestations was significantly associated with pleuro-pulmonary disease (p = 0.001). Pulmonary affection was significantly associated with number of drug intake (p = 0.003). Chest infection was significantly related to the presence of other non pleuro-pulmonary infections (p = 0.034). Pulmonary infections were more evident in patients with pleural effusion (P

Background The hepatitis C virus (HCV) epidemic is particularly devastating in Egypt where its prevalence is about 12%. Chronic HCV infection can result in the accumulation of immune complexes and stimulate antibodies, which can result in extrahepatic manifestations (EHM). Aim of the work To assess the efficacy and safety of combined pegylated interferon and ribavirin therapy in the management of rheumatological EHM in HCV patients. Patients and methods Twenty-seven out of 50 consecutive HCV patients with rheumatologic EHM were eligible and included in this study. All patients included in this study were subjected to full history taking, clinical examination and laboratory investigations. Results The mean age of the patients was 43.8 ± 7.6 years. The clinical response of the patients was: 2 patients (7.4%) were complete clinical responders, 5 (18.5%) were partial responders, 3 (11.1%) showed relapse and 17 (63%) were non-responders. There was a significant improvement in the number of patients with fatigue, polymerase chain reaction positivity and elevated liver enzymes ( p p p = 0.03, p = 0.01 respectively). There was no significant correlation between virological and clinical responses. There was a significant correlation between virological and biochemical responses ( p = 0.02). Minor side effects of the AVT developed in 13 (48.1%) patients: anemia ( n = 5), mild thrombocytopenia ( n = 8), flu-like symptoms ( n = 7) and mild depression ( n = 1). Conclusion Peg IFN and ribavirin did not improve HCV rheumatological extrahepatic manifestations. Antiviral treatment may also induce or worsen autoimmune disorders and is sometimes associated with major immune-mediated adverse events.

There are scanty data on the prevalence of vitamin D deficiency and its relation to disease activity among patients with juvenile-onset systemic lupus erythematosus (JoSLE) in the Middle East and North Africa, an area known to be endemic for vitamin D deficiency and insufficiency. The aim of this study was, therefore, to study vitamin D status and its relation to disease activity and parameters in Egyptian patients with JoSLE. Serum levels of 25(OH) D3 in 70 JoSLE patients were compared to 40 age-, sex-, and body mass index-matched healthy controls. The 25(OH) D3 was determined by enzyme-linked immunosorbent assay. Information regarding the medical history, clinical symptoms, and signs was registered at the time of serum sampling. Disease activity of SLE was evaluated according to the SLEDAI score. The mean level of serum 25(OH) D3 was 12 ± 3.7 in JoSLE patients compared to 21 ± 3.5 ng/mL in normal controls (p0.001). Forty percent (28/70) of the JoSLE patients has severe 25(OH) D3 deficiency (≤10 ng/mL), and 60 % of the JoSLE patients has 25(OH) D3 insufficiency (≤30 ng/mL). None of the JoSLE patients has 25(OH) D3 level30 ng/mL. There was no significant correlation between serum levels of 25(OH) D3 and the demographic data, medication used, and some laboratory data of patients with JoSLE. Disease activity score in our patients was insignificantly correlated with serum levels of 25(OH) D3. In spite of vitamin D supplementation in Egyptian JoSLE patients and the presence of vitamin D insufficiency in the control group, there are still significantly lower levels of vitamin D in JoSLE compared to normal controls.

Aim of the workTo study the prevalence of anti-HCV antibodies among patients suffering from systemic lupus erythematosus (SLE) as well as to determine the impact of chronic HCV infection on the clinical manifestations and disease activity.Patients and methodsNinety-eight consecutive SLE patients presented to the rheumatology department, Cairo University Hospitals were included in the study. All patients were screened for anti-HCV antibodies using a 3rd generation enzyme-linked immune-sorbent assay (ELISA). Patients with positive anti-HCV were tested for the presence of HCV-RNA by polymerase chain reaction (PCR). Patients were classified into two groups; HCV/SLE and non-HCV/SLE according to the presence or absence of anti-HCV antibodies.ResultsTwenty/98 patients (20.4%) were positive for HCV antibody. Eight/98 patients (8.2%) had active viremia. SLE patients with positive anti-HCV antibodies tend to be older in age and having a longer SLE duration than non-HCV/SLE Patients. HCV/SLE patients had significantly lower mucocutaneous manifestations (p

Although the prevalence of RA in the Middle East and Africa is comparable with that in other parts of the world, evidence indicates that its management in this region is suboptimal for a variety of reasons, including misconceptions and misunderstandings about the disease's prevalence and severity in the region, compounded by the lack of local epidemiological and health-economic data around the disease; the perception that RA is a low priority compared with other more prevalent conditions; delayed diagnosis, referral and treatment; and a lack of a region-specific, evidence-based management approach. In the absence of such an approach, the EULAR treatment recommendations may provide a useful starting point for the creation of guidelines to suit local circumstances. However, although agreement with the EULAR recommendations is high, many barriers prevent their implementation in clinical practise, including lack of timely referral to rheumatologists; suboptimal use of synthetic DMARDs; poor access to biologics; lack of awareness of the burden of RA among healthcare professionals, patients and payers; and lack of appropriate staffing levels.To optimise the management of RA in the Middle East and Africa, will require a multi-pronged approach from a diverse group of stakeholders-including local, national and regional societies, such as the African League of Associations in Rheumatology and International League of Associations for Rheumatology, and service providers-to collect data on the epidemiology and burden of the disease; to increase awareness of RA and its burden among healthcare professionals, payers and patients through various educational programmes; to encourage early referral and optimise use of DMARDs by promoting the EULAR treatment recommendations; to encourage the development of locally applicable guidelines based on the EULAR treatment recommendations; and to facilitate access to drugs and the healthcare professionals who can prescribe and monitor them.

Background Thrombotic thrombocytopenic purpura is a potentially lethal microvascular thrombotic disorder. Case presentation In this study, we report a 32 years old woman who suffered from undifferentiated vasculitis with marked improvement on steroids and cyclophosphamide. Two years later, hepatitis C virus infection was discovered. Decision for interferon therapy was not recommended at this stage and the patient remained stable for the following 7 years. In January 2009, pegylated interferon and ribavirin were started due to worsening of her hepatitis; the treatment was stopped after 12 weeks due to the absence of any virologic response. Fourteen months later, she developed severe uncontrolled thrombotic thrombocytopenic purpura that led eventually to her death. Conclusion We report this rare case of thrombotic thrombocytopenic purpura that may directly be related to chronic HCV infection rather than to interferon therapy.

The objective of the study is to screen 12 MEFV gene mutations in Egyptian patients with familial Mediterranean fever (FMF) and to study the initial hypothesis that the phenotypic expression of the disease may be attributable to the existence of a particular mutation. We enrolled 136 Egyptian patients (74 males, and 62 females) with a clinical diagnosis of FMF. DNA was amplified by PCR and subjected to reverse hybridization for the detection of 12 MEFV gene mutations. The phenotypic expression of the disease was compared in two subgroups according to the presence of homozygote E148Q and M694V gene mutations. The most frequent gene mutations in the studied group were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6%, respectively. At least one of these main five founder mutations was present in 132 patients (97.1%). Thirty-two patients (23.5%) were homozygote for one of the main five founder mutations. The most common homozygote gene mutations were E148Q and M694V, each in 12 patients (8.8%). Significant increase in abdominal pain and arthritis was found in patients with homozygote M694V mutation compared to those with E148Q mutation. All patients with amyloidosis had M694V gene mutation. The increased frequency of V726A gene mutation and the rarity of amyloidosis in this study suggest that Egyptian patients may have a milder form of FMF compared to other populations. The five main founder mutations account for the vast majority of cases of FMF. M694V gene mutation may be associated with increased frequency of abdominal pain, arthritis and the presence of amyloidosis.

Objective: To compare the validity and reliability of a graphic rating scale (GRS) and a verbal rating scale (VRS) for measuring pain intensity in young female Egyptian and Dutch patients with rheumatoid arthritis (RA). Methods: Data were obtained in a cross-cultural study of 42 Egyptian and 30 Dutch female outpatients with stable RA. Construct validity was assessed by correlating the scales with other core measures of disease activity in RA. Test-retest reliability was assessed over a 1-week interval. Results: The GRS and the VRS were strongly intercorrelated in the total study cohort and in the Egyptian and Dutch subgroups. In the individual subgroups, only the GRS demonstrated the expected pattern of correlations with other disease activity measures. Test-retest reliability of the GRS was adequate in both Egyptian and Dutch patients (intraclass correlation coefficient 0.78 vs. 0.83, respectively), whereas reliability of the VRS was unsatisfactory in the Egyptian subgroup (weighted [kappa] 0.60 vs. 0.82 in the Netherlands). Discussion: The study confirmed that the GRS and VRS were reliable and valid in the total study cohort. Within the individual countries, the GRS seemed to perform better than the VRS.

Early diagnosis and early initiation of disease-modifying antirheumatic drug (DMARD) therapy slow the progression of joint damage and decrease the morbidity and mortality associated with rheumatoid arthritis (RA). According to the European League Against Rheumatism (EULAR) guidelines, treatment should be initiated with methotrexate and addition of biological DMARDs such as tumour necrosis factor (TNF) inhibitors should be considered for RA patients who respond insufficiently to methotrexate and/or other synthetic DMARDs and have poor prognostic factors. Africa and the Middle East is a large geographical region with varying treatment practices and standards of care in RA. Existing data show that patients with RA in the region are often diagnosed late, present with active disease and often do not receive DMARDs early in the course of the disease. In this review, we discuss the value of early diagnosis and remission-targeted treatment for limiting joint damage and improving disease outcomes in RA, and the challenges in adopting these strategies in Africa and the Middle East. In addition, we propose an action plan to improve the overall long-term outlook for RA patients in the region.

To study the prevalence of anti-HCV antibodies among patients admitted to the rheumatology department, Cairo University hospitals, in 6-month period as well as to determine whether chronic HCV infection was the primary cause of their admission or just a concomitant association with the rheumatic disease. One hundred and fifty-seven patients were included in this study. They represent all patients admitted to the rheumatology inpatient department of Cairo University hospitals during the study period. Preset questionnaire including detailed demographic data, cause of admission and clinical manifestations of their disease was obtained for every patient. All patients were screened for HCV antibodies using ELISA technique. Other laboratory and imaging investigations were done according to the patient’s diagnosis. Twenty-nine patients (18.5%) were positive for HCV antibody. Eleven patients of them (38%) were admitted due to rheumatic manifestations directly related to chronic HCV infection, which represent 7% of all admitted patients (11/157). HCV antibodies were found in 17.6 and 6.7% among patients with rheumatoid and systemic lupus erythematosus. Arthritis, palpaple purpura, digital gangrene and mononeuritis multiplex were the most common causes of admission related to chronic HCV infection. HCV antibodies were found in 18.5% among admitted patients to the rheumatology ward. The rheumatic manifestations of chronic HCV represent the primary cause of admission in 7% of all admitted patients. HCV screening should be included in the routine investigations for patients presenting to rheumatology departments in countries with high prevalence of chronic HCV infection.

it has been suggested that patients from Mediterranean cultures tend to report more intense pain than their Northern or Western European counterparts in comparable medical conditions. However, empirical data to support this hypothesis are limited. The goals of the present study were to examine differences in pain intensity reports between Dutch and Egyptian women with rheumatoid arthritis (RA) and to examine the influence of possible confounding variables using multivariate analyses. We performed a cross-sectional study in 30 Dutch and 42 Egyptian women with comparable RA, matched for age and disease duration. Pain intensity was measured on a 100-mm graphic rating scale. Additionally, we assessed physical function, radiographic joint damage, progression of RA, disease activity, number of swollen and tender joints, medication, rheumatoid factor, and socioeconomic variables. The progression of RA and radiographic damage were not significantly different between Egyptian and Dutch patients. However, the Egyptian population reported significantly worse pain and physical function and demonstrated higher disease activity. Multiple linear regression analysis showed that the country of residence and the number of tender and swollen joints were significant independent determinants of pain reports. The results provide some support for the idea that there are ethnocultural differences in pain reports between Egyptian and Dutch women with RA, although the mechanisms underlying these differences remain unclear. Perspective: This article shows that after controlling for differences in demographic, socioeconomic, and clinical variables, Egyptian women with RA reported more pain than Dutch women with RA. Clinicians and investigators should recognize that cultural or ethnic factors may play an important role in patients' pain reports. (C) 2007 by the American Pain Society

To highlight the clinical, radiological, and pathological presentations of 10 Egyptian patients with camptodactyly, arthropathy, coxa vara, and pericarditis (CACP) syndrome. Methods. Ten cases underwent a full history, complete clinical examination, laboratory and radiological investigations (and magnetic resonance imaging, MRI, of knee joints); arthroscopic histopathological synovial studies were performed in 6 cases. Results. Camptodactyly and large joint arthropathies were present in all cases. The onset was at birth in 5 cases, and consanguinity was present in all cases. Laboratory investigations were normal in all cases (normal complete blood cell count, erythrocyte sedimentation rate, absent rheumatoid factor, and antinuclear antibody). Synovial fluid analyses were acellular in 3, hypocellular in 4, and moderately cellular in 2 cases. Histopathology revealed noninflammatory synovial hyperplasia in the 6 synovial biopsies obtained, with multinucleated giant cells in 4 of them. Plain hip radiology revealed short broad femoral neck and widening of joint space in all cases, with coxa vara in 9 cases. MRI of the knees showed rim-like enhancement of the lining of the fluid filled bursae in 7 cases, and homogenous enhancement pattern in 2 cases. No evident cartilage destruction existed in any case.Our cases represent a familial syndrome of noninflammatory arthropathies associated with camptodactyly and coxa vara. The complete picture of the syndrome may be related to disease duration, and MRI is a useful tool in diagnosis. Physicians should be aware of the syndrome, to avoid misdiagnosis with other pediatric connective tissue diseases.

A total of 120 patients with moderate to severe pain due to localized rheumatic or traumatic conditions participated in a double-blind, randomized trial. Patients were randomly allocated to receive ultrasonic sessions three times weekly for 4 weeks, using either diclofenac in a gel base (Voltaren Emulgel®) or regular gel as a coupling medium. A statistically significant ( P < 0.01) improvement was achieved in both treatment groups in most of the evaluation criteria by the end of the first week. Treatment was prematurely discontinued due to complete cure in 60% of patients using Voltaren Emulgel® compared with only 15% of those using regular gel ( P < 0.01). Physician's assessment of complete relief of pain was also statistically significant ( P < 0.01) in favour of Voltaren Emulgel® throughout the trial period and the physician's overall assessment of therapeutic efficacy revealed that a satisfactory result was achieved in 86% of Voltaren Emulgel®-treated patients compared with 76% of patients receiving regular gel ( P < 0.05). Tolerability was good or excellent in over 95% of patients in both treatment groups. The results of the study strongly suggest that the use of Voltaren Emulgel® as a coupling medium during ultrasonic therapy is a preferable, effective alternative to the currently used regular gel.

Aim of the workTo study the mean platelet volume (MPV) in children with juvenile-onset SLE (Jo-SLE), and whether MPV can be used as a biologic marker for disease activity or flare.Patients and methodsTwenty-nine patients from the rheumatology outpatient clinic, Pediatric Cairo University Hospitals and age 36 and gender matched healthy controls were included in the study. The MPV was determined within 4h of blood sampling in all study populations. Recent routine laboratory investigations for Jo-SLE patients were obtained. Disease activity was estimated using SLE disease activity index (SLEDAI).Results29 Jo-SLE patients had a mean age of 12.8±2.9years and disease duration of 3.5±3year. The most frequent clinical manifestations were photosensitivity, malar rash, followed by arthritis and serositis. The MPV in Jo-SLE patients was 8.2±2.1femtoliters (fL) compared with 5.6±0.9fL in healthy controls (p

A study of the effectiveness of physical therapy for patients with myofacial pain dysfunction syndrome was performed. Clinical evaluation of 120 patients revealed marked male preponderance, distribution according to age showed a great prevalence of the third decade, and most common chief complaints were pain and muscle tenderness. Patients were classified randomly into three equal groups treated by muscle relaxant drugs, shortwave diathermy, and ultrasonic therapy, respectively. Regular follow-up was carried out for 6 to 12 months to assess patients' responses to different forms of treatment. Evaluation revealed marked relief of symptoms by the use of physical therapy, and the best results were obtained by the use of ultrasonic therapy.