Dexamethasone Pulse Therapy Research Articles

The impact of different corticosteroids in hospitalised patients with severe COVID-19 pneumonia: a retrospective observational study

Background: The COVID-19 pandemic created havoc on health care systems and economies worldwide. Corticosteroids have been shown to be effective in the management of COVID-19. Methods: A retrospective observational study was conducted on 311 patients meeting the inclusion criteria at the Augustus Long Hospital, Trinidad and Tobago between July-December 2021. Data was classified into three treatment groups: low dose dexamethasone, high dose dexamethasone and methylprednisolone pulse therapy. The primary outcomes were the 28-day mortality and need for invasive mechanical ventilation and the secondary outcome was the length of hospital stay. The patient cohort was also classified into simple oxygen and high flow oxygen groups and a subgroup analysis was also performed. Results: There were no significant statistical differences between age, gender, vaccination status and co-morbidities between the treatment groups. However, there were significant differences in the ethnic ratios amongst the high dose dexamethasone and methylprednisolone treatment groups (East Indians to Africans; 61.7%vs. 37%; 72.9% vs.25.4% respectively; p=0.02). In patients receiving simple oxygen on admission, those who were treated with low dose dexamethasone when compared to high dose dexamethasone and methylprednisolone, had the lowest 28-day mortality (15.3% vs. 40.9% vs. 40% respectively; p< 0.001), lowest need for IMV (0.7% vs. 9.1% vs. 40% respectively; p< 0.001) and the shortest length of hospital stay (median [IQR] days; 7[12-5], 11[22-7], 16[27-14] respectively; p< 0.001). In patients receiving high flow oxygen, those treated with methylprednisolone had the lowest 28-day mortality (45.8%), when compared to the high dose dexamethasone (59.5%) and low dose dexamethasone (81%) groups; however, these results were not statistically significant (p = 0.053). Conclusion: In our study, patients receiving simple oxygen had better clinical outcomes when treated with low dose dexamethasone compared to higher dose corticosteroids. Methylprednisolone pulse therapy may be beneficial in patients requiring high flow oxygen; but further studies are needed.

Dexamethasone-cyclophosphamide pulse therapy outcomes comparing pemphigus vulgaris and pemphigus foliaceus groups in a Brazilian cohort study

BackgroundDexamethasone-cyclophosphamide pulse (DCP) and dexamethasone pulse (DP) have been successfully used to treat pemphigus, but DCP/DP outcomes comparing pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are scarce. ObjectiveTo compare DCP/DP outcomes in a Brazilian cohort of PV and PF patients according to demographic and clinical data. MethodsRetrospective analytical cohort study, reviewing medical charts of PV and PF patients (for DCP/DP Phases I‒IV consult Pasricha et al.16‒18). Results37 PV and 41 PF patients non responsive to usual treatments were included similarly for DCP or DP therapy. Disease duration was longer among PF before DCP/DP prescription (p < 0.001); PF required a higher number of monthly pulses to acquire remission in Phase I (median 10 and 6 pulses, respectively; p = 0.005). DCP/DP outcomes were similar in both groups: remission in 37.8% of PV and 34.1% of PF after completed DCP/DP cycles following a median of 13 months (1–56 months follow-up); failure occurred in 13.5% of PV and 14.6% of PF in Phase I; relapse in 13.5% of PV and 12.2% of PF, and dropout in 27% of PV and 24.4% of PF in Phases II to IV. Mild side effects were documented. Study limitationsThe severity of PV and PF disease was not assessed by score indexes. ConclusionsPV and PF patients presented similar DCP/DP outcomes. DCP/DP should be initiated earlier in PF patients due to the longer duration of their disease in order to decrease the number of pulses and the duration of Phase I to acquire remission.

Dexamethasone Pulse Therapy with Multisystem Inflammatory Syndrome in Children: Case Series

Objective: Study aimed to describe the effect of dexamethasone pulse therapy by assessing its efficacy on patients infected with COVID-19 complicated with MIS-C. Methods: This is single center, retrospective case series study that was conducted in Saudi Arabia. We report all eligible patients who diagnosed with MIS-C and received pulse therapy of dexamethasone during COVID-19 pandemic from 2020-2022. The study endpoints were success to wean or extubate the patient and discharge from the PICU. Results: Three patients were included in this report. All three patients received dexamethasone pulse therapy were successfully improved. After five to seven days were discharged from PICU. Conclusion: Our clinical experience suggests that the efficacy of dexamethasone with MIS-C as alternative to methylprednisolone could be effective.

Extended vincristine and dexamethasone pulse therapy may not be necessary for children with TCF3-PBX1 positive acute lymphoblastic leukaemia.

The effect of prolonged pulse therapy with vincristine and dexamethasone (VD) during maintenance therapy on the outcome of paediatric patients with TCF3-PBX1 positive acute lymphoblastic leukaemia (ALL) remains uncertain. We conducted non-inferiority analysis of 263 newly diagnosed TCF3-PBX1 positive ALL children who were stratified and randomly assigned (1:1) to receive seven additional VD pulses (the control group) or not (the experimental group) in the CCCG-ALL-2015 clinical trial from January 2015 to December 2019 (ChiCTR-IPR-14005706). There was no significant difference in baseline characteristics between the two groups. With a median follow-up of 4.2 years, the 5-year event-free survival (EFS) and 5-year overall survival (OS) in the control group were 90.1% (95% confidence interval [CI] 85.1-95.4) and 94.7% (95% CI, 90.9-98.6) comparable to those in the experimental group 89.2% (95% CI 84.1-94.7) and 95.6% (95% CI 91.8-99.6), respectively. Non-inferiority was established as a one-sided 95% upper confidence bound for the difference in probability of 5-year EFS was 0.003, and that for 5-year OS was 0.01 by as-treated analysis. Thus, omission of pulse therapy with VD beyond one year of treatment did not affect the outcome of children with TCF3-PBX1 positive ALL.

Dexamethasone Pulse Therapy in Pemphigus Vulgaris Associated Myocardial Infarction in Resource-Limited Settings

Pemphigus vulgaris is an autoimmune blistering disorder where biologics are the cornerstone of therapy. In resource-limited settings, a dermatologist should rely on systemic steroids. Dexamethasone pulse therapy is a cheap and established treatment of pemphigus where a supra-pharmacological dose of dexamethasone is used. High dose of dexamethasone is supposed to have atherogenic potential which could promote a hypercoagulable state. Here, we report a case of a 30-year-old woman in the resource-limited setting of Nepal, who was under monthly dexamethasone pulse therapy for pemphigus vulgaris, who had an acute episode of ST-segment elevated myocardial infarction. In such setting, although steroids are the cornerstone of therapy in various disorders, physicians should be equally cautious in using a high dose of steroids which might lead to fatal complications. This could probably be the first case report of steroid-induced acute myocardial infarction during treatment of pemphigus worldwide.

Short-Term Safety and Efficacy of Onasemnogene Abeparvovec in 10 Patients with Spinal Muscular Atrophy: Cohort Study

Background. The efficacy and safety of onasemnogene abeparvovec have been demonstrated in patients with spinal muscular atrophy (SMA) in several clinical and observational studies. Gene replacement therapy results in Russian patients with SMA is not investigated yet.Objective. The aim of the study is to study the safety and efficacy of onasemnogene abeparvovec in children with SMA in real clinical practice.Methods. The study included patients with proximal 5q SMA administered with onasemnogene abeparvovec. Diagnosis was verified by biallelic deletion in the 7th exon of the SMN1 gene. Gene replacement therapy was administered according to the decision of neurologists consensus in case of the absence of antibodies to the adeno-associated serotype 9 virus. The therapy safety was estimated via clinical and laboratory data from the hospital (at least 7 days) and from outpatient departments (at least 60 days). Efficacy was estimated via CHOP INTEND scale and mastering new motor skills ≥ 6 months after therapy onset.Results. Treatment outcomes were studied in 10 SMA patients aged 19 months (15; 21). All patients developed at least one clinical manifestation (hyperthermia, vomiting, lethargy and/or loose stool) associated with drug administration during the first week of follow-up. Increased hepatic transaminases activity and monocytosis was recorded in all patients, thrombocytopenia — in 9, neutropenia — in 5, increased troponin I concentration — in 3. In three cases it was necessary to increase the oral prednisolone dose of to 2 mg/kg, in one case — the dexamethasone pulse therapy dose. The therapy efficacy was monitored ≥ 6 months after therapy onset via the CHOP INTEND scale in 2 patients (scores increased by 32 and 19 points, respectively), and via mastering new motor skills in 8 patients (positive dynamics was noted in 7 cases).Conclusion. The onasemnogene abeparvovec is relatively safe and quite effective for using in real clinical practice

Severe COVID-19 along with Cytokine Storm in Pemphigus Vulgaris Managed Successfully with Dexamethasone Pulse Therapy.

How to cite this articlePradhan S, Kumar N, Kumar S. Severe COVID-19 along with Cytokine Storm in Pemphigus Vulgaris Managed Successfully with Dexamethasone Pulse Therapy. Indian J Crit Care Med 2021;25(11):1320–1321.

A study on the outcome of pulse therapy in vesicobullous disorders at a tertiary care centre in Chidambaram, Tamilnadu

Introduction: With the advent of pulse therapy and adjuvant immunosuppressive drugs, the outcome and prognosis of vesicobullous disorders have been improved to a greater extent. Different regimen protocol has been tried and this descriptive study was carried out to assess the outcome of various pulse therapy regimens in vesicobullous disorder at our centre. Methods: A total of 26 vesicobullous patients were enrolled for the study. Diagnosis was made clinically and confirmed by histopathology. They received treatment with Dexamethasone-Cyclophosphamide pulse (DCP) or Dexamethasone -Azathioprine pulse (DAP) or Dexamethasone pulse (DP) therapy and were followed up for clinical remission and side effects of therapy. Results: There was a total of 26 patients comprising 69.23% females and 30.77% males and 50% were between the age group of 40-50 years. Pemphigus vulgaris was the commonest clinical type seen in 69.23%.DCP was given for 22(84.62%) patients, dexamethasone pulse in 3(11.54%) and DAP in one (3.85%). In DCP group 77.27% of patients were in Phase I and 22.73% achieved clinical remission. One patient was refractory to DCP and required rituximab infusion. Weakness, headache, vomiting and weight gain were the commonest side effects encountered in our study. Avascular necrosis of femur and reactivation of pulmonary tuberculosis were the major side effects noticed in one patient each. Conclusion: DCP therapy prove to be an excellent therapeutic regimen in case of vesicobullous disorders to attain faster recovery sparing the adverse effect of corticosteroids. DAP can be an useful therapeutic option in patients who were unmarried or in reproductive age group. Keywords: Pemphigus vulgaris, Dexamethasone-cyclophosphamide pulse. Dexamethasone-azathioprine pulse, Dexamethasone pulse

Sweet’s syndrome: A Therapeutic challenge

Sweet’s syndrome: A Therapeutic challenge - IJCED- Print ISSN No: - 2581-4710 Online ISSN No:- 2581-4729 Article DOI No:- 10.18231/j.ijced.2019.037, IP Indian Journal of Clinical and Experimental Dermatology-IP Indian J Clin Exp Dermatol

Pyoderma gangrenosum with Takayasu's arteritis: A rare association

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by destructive, necrotizing, and noninfective ulceration of skin which most commonly involve lower extremities. We are reporting a case of 20-year-old male who presented with multiple nodulo-ulcerative plaques on both thighs which showed histopathological findings of granulomatous reaction. He was initially treated ineffectively with anti-tubercular agents. Following a revised diagnosis of PG, dexamethasone pulse therapy (100 mg daily for 3 consecutive days in a month) was initiated and the lesions improved with three such pulses. However, the patient was lost to follow-up. The patient presented a year later with relapse and pulse therapy was restarted. Incidental finding of absence of peripheral pulse and nonrecordable blood pressure on left upper limb led to the diagnosis of Takayasu's arteritis (TA). Skin lesions improved and the patient was referred for the management of TA. Association of PG with TA is rare and very few cases have been reported from India till date.

Pyoderma gangrenosum: A clinico-epidemiological study.

Pyoderma gangrenosum is a neutrophilic dermatosis of unknown etiology, with inconstant systemic associations and a variable prognosis. To study the clinical features and systemic associations of pyoderma gangrenosum and its response to treatment. All patients diagnosed to have pyoderma gangrenosum at the dermatology department of the Government Medical College, Kozhikode, from January 01, 2005 to December 31, 2014 were included in this prospective study. During the 10-year study period, 61 patients were diagnosed to have pyoderma gangrenosum. A male predilection was noted. The most common clinical type was ulcerative pyoderma gangrenosum (90.2%). More than 60% of patients had lesions confined to the legs; 78.7% had a single lesion and 27.9% had systemic associations. Most patients required systemic steroids. Patients with disease resistant to steroid therapy were treated with intravenous immunoglobulin G and split-thickness skin grafts under immunosuppression induced by dexamethasone pulse therapy. All except one patient attained complete disease resolution. The main limitation of our study was the small sample size. The male predilection documented by us was contrary to most previous studies. We found split-thickness skin graft to be a useful option in resistant cases. More prospective studies may enable the formulation of better diagnostic criteria for pyoderma gangrenosum and improve its management.

Comparative Efficacy of Low-Dose Oral Corticosteroids and Oral Mini Pulse Dexamethasone in Patients of Vitiligo

Introduction: Vitiligo is a common, acquired, discoloration of the skin with unknown etiology. There are numerous treatment options available for vitiligo, but none is universally effective. Systemic corticosteroids suppress immunity and lead to repigmentation but produce unacceptable side effects. Oral corticosteroid low dose treatment may be associated with fewer side effects than usual dose-treatment. Several data also showed that oral dexamethasone pulse treatment was effective in arresting progression of vitiligo yet fails to induce satisfactory repigmentation in the great majority of their patients.Objectives: A clinical trial was carried out to compare the efficacy of low-dose oral corticosteroids and oral mini pulse dexamethasone in patients of vitiligo.Materials and Methods: The study was conducted in the Department of Dermatology and Venereology, Combined Military Hospital (CMH), Dhaka, Bangladesh during January 2013 to December 2013. Total sixty patients of vitiligo were enrolled and divided into group A and group B. Thirty of group A patients were treated with oral prednisolone daily and thirty of group B patients were treated with oral dexamethasone pulse therapy weekly.Results: Out of sixty patients of vitiligo, maximum patients of both groups had progressive type of vitiligo. In Group-A, the duration of illness was an average of 10 months and in group-B, it was an average of 8.20 months. Single lesion was 15 (50%) for Group-A and 14 (46.7%) for Group-B. Multiple lesions were 15 (50%) &amp; 16 (53.6%) for Group-A and Group-B respectively. The study showed that improvement rate was highest for the lesions on the extremities, which was 18 (34.6%) and lowest for back 03 (5.8%). Out of all patients from Group-A, the mean size of the lesions were 8.17cm, 5.90 cm, 4.32 cm and 3.57 cm at 1st visit, 2nd visit, 3rd visit and 4th visit respectively. In Group-B, the mean sizes of the lesions were 7.50 cm, 4.92 cm, 3.00 cm, and 4.75 cm at 1st visit, 2nd visit, 3rd visit and 4th visit respectively. Among the patients 27 (90%) of group-A and 25 (83.3%) of group B were improved after 16th week of treatment, slight response 4(13.3%) and 6(20%), moderate response 22(63.2%) and 18(59.4%) and marked response was 1(3.3%) and 1(3.3%) in group A and group B respectively.Conclusion: The study concluded that both the drugs, oral prednisolone and dexamethasone when used individually, were found to be equally effective in the treatment of vitiligo.Journal of Armed Forces Medical College Bangladesh Vol.11(1) 2015: 54-58

Clinical profiles and treatment outcomes of systemic corticosteroids for toxic epidermal necrolysis: A retrospective study.

Toxic epidermal necrolysis (TEN) is an uncommon severe cutaneous adverse reaction. Although controversies remain in the pathophysiology and management of this condition, improvements in survival and morbidity have been observed over the past decade. The aim of the present study was to demonstrate the clinical profiles of TEN in Thai patients and the treatment outcome with dexamethasone pulse therapy assessed by using the Severity of Illness Score for Toxic Epidermal Necrolysis (SCORTEN). Medical records of all patients with TEN were collected retrospectively from January 2002 to December 2012. Epidemiological features, etiologies, treatments and clinical outcomes were reviewed. Of 18 patients, the female to male ratio was 1:1 and the mean age was 49.7years. Cephalosporins (27.8%), phenytoin (16.7%), carbamazepine, sulfonamide drugs and allopurinol (11.1% each) were implicated as leading causes of TEN. Hepatitis was the most frequent complication (77.8%). Pulsed high doses of dexamethasone 1-1.5mg/kg per day for a short period were administrated in all cases. Two of the 18 patients receiving corticosteroids (SCORTEN 5 and 6) died. The mortality rate was 11% (2/18 patients), however, no patient receiving systemic corticosteroids died if the patients had less than 4points on SCORTEN. The clinical features of Thai patients with TEN were similar to other reports. In conclusion, in addition to withdrawal of the suspected agent and intensive supportive care, the administration of short-term dexamethasone pulse therapy, particularly during the initial phase, may be beneficial in reducing the mortality rate.

A rare pulmonary complication of myeloma therapy

A 77-year-old Caucasian female was referred to the renal team with a newly elevated plasma creatinine (288 mmol·L−1) associated with a 2-week history of malaise. Urinalysis demonstrated heavy proteinuria and renal biopsy confirmed the diagnosis of myeloma kidney. She was commenced on pulsed dexamethasone therapy (20 mg for 4 days in succession) before commencing thalidomide 50 mg daily. On day 10 of therapy, she was admitted to hospital with gradually progressive breathlessness for the previous 24 h, present at rest but made worse by exertion. She described a dry cough and ill-defined discomfort bilaterally over the thoracic cage. No haemoptysis was reported. Examination revealed reduced oxygen saturations of 85% on room air and a respiratory rate of 20 breaths·min−1. Auscultation of the chest disclosed bilateral scattered crackles. She had a trace of pitting peripheral oedema only and the jugular venous pressure was not elevated. A plain chest radiograph was taken and is shown in figure 1. Figure 1 Chest radiograph Task 1 How would you interpret the chest radiograph? Answer 1 There are coarse bilateral patchy infiltrates affecting all the visualised lung fields with relative sparing of the right costophrenic angle. The cardiothoracic ratio on this posterioranterior film is preserved. There is no radiological evidence of congestive cardiac failure. The appearances are in keeping with a diffuse interstitial process, with a wide differential diagnosis. Comparison to a plain chest radiograph taken a month earlier shows these to be new abnormalities. A blood gas analysis was performed. This revealed an oxygen tension ( P O2) of 6.93 kPa (52 mmHg) and carbon dioxide tension ( P CO2) of 3.06 kPa (23 mmHg) on an inspired oxygen fraction of 0.21 (room air). Task 2 What is the alveolar-arterial (A-a) gradient and arterial/alveolar (a/A) ratio? How would you interpret these figures? …

Randomized double‐blind study of the effect of dexamethasone and methylprednisolone pulse in the control of rheumatoid arthritis flare‐up: a preliminary study

The objective of this study was to compare the efficacy and safety of dexamethasone and methylprednisolone for pulse therapy of rheumatoid arthritis flare-up. This randomized double-blind controlled study was performed in the Emam Reza Educational Hospital of Tabriz University of Medical Sciences, Tabriz, Iran. Thirty rheumatoid arthritis patients who had severely active disease were recruited to the dexamethasone and methylprednisolone pulse groups. Disease activity of all the patients was measured by the Disease Activity Score in 28 joints (DAS28) at baseline, and days 4 and 30. The differences in the DAS28 at days 4 and 30, and the number of patients whose DAS28 obtained less than 3.2 and 2.6 in the dexamethasone and methylprednisolone groups were non-significant. There was not any significant difference between the adverse effects of the treatments in the two groups. The results of the study suggest that dexamethasone pulse therapy is a safe and effective treatment for severe rheumatoid arthritis flare-up.

Acute Encephalopathy Associated with Human Metapneumovirus Infection

We encountered a 3.5-year-old girl with acute encephalopathy associated with human metapneumovirus (hMPV) infection. She had pyrexia and status epilepticus, followed by a coma. Cerebrospinal fluid analysis showed no pleocytosis or elevation of protein levels. hMPV RNA was detected in tracheal aspirate. Acute encephalopathy in the patient was probably related to the hMPV infection. Serum levels of interleukin-6 and matrix metalloproteinase-9 were elevated on admission, and these factors were presumed to be related to acute encephalopathy, associated with her viral infection, or due to status epilepticus. She was treated with dexamethasone pulse therapy, intravenous immunoglobulin, and continuous thiopental infusion. She recovered without neurological sequelae.

Factors affecting the duration of phase I of dexamethasone - cyclophosphamide pulse therapy.

The introduction of dexamethasone-cyclophosphamide pulse (DCP) therapy for the pemphigus group of disorders by Pasricha has revolutionized the therapy for pemphigus. There are very few studies regarding factors affecting duration of phase I of the DCP. Our purpose was to study the relationship between various factors and duration of the phase I. A retrospective study of 98 patients of pemphigus on Dexamethasone Pulse therapy was conducted. Patients were classified according to duration of Phase 1 as those with phase I less than 6 months and those more than 6 months and analyzed for variable factors affecting duration of phase I. Disease severity in pemphigus significantly prolonged the duration of phase I of DCP. Longer duration was also observed in patients on concurrent oral steroid therapy (both statistically significant). The findings from our study help us to address patient expectations and apprehensions regarding duration of therapy. A detailed understanding of the various patient and disease related factors responsible for affecting Phase I duration will help in better management of the patient, and the disease.

P.14.10 Respiratory failure as presenting symptom of paraneoplastic necrotizing autoimmune myopathy

Necrotizing autoimmune myopathy (NAM) is associated with cancer, connective tissue disorders, and statin use. Respiratory failure as a presenting symptom has been reported in rare cases of other inflammatory myopathies, but not in NAM. A 48-year-old woman was acutely admitted with severe hypercapnia which required immediate endotracheal intubation. History revealed that she experienced shortness of breath since one month. Her past medical history included a mastectomy 2years prior to admission, because of noninvasive ductal mammacarcinoma. On admission there was mild symmetrical proximal weakness of her arms and legs and slightly more pronounced distal weakness of her legs, as well as weakness of her neck flexor muscles, which in retrospect had been gradually progressive in the weeks before presentation. Serum creatine kinase activity was five times the upper limit of normal and electromyography exhibited extensive myopathic changes. Magnetic resonance imaging (T2 weighted images) showed hyperintensity of the pelvic girdle and proximal leg muscles. Muscle biopsy showed extensive muscle fibre necrosis in the absence of inflammatory cells. Myositis immunoblot did not show myositis specific antibodies. A diagnosis of paraneoplastic NAM was made and monthly courses of oral dexamethasone pulse therapy was started which led to prompt extubation and remarkable recovery of muscle strength in weeks. Acute respiratory failure can be a presenting symptom in paraneoplastic necrotizing autoimmune myopathy. Paraneoplastic NAM should be considered in all patients with (sub) acute onset of symmetrical and progressive limb weakness and a history of malignancy. Immunosuppressive therapy can lead to substantial recovery.

Pulse therapy in pemphigus: report of 11 cases

In this study, five cases of pemphigus vulgaris and two cases of pemphigus foliaceus were treated with cyclophosphamide pulse therapy associated with prednisone, resulting in the need for a smaller maintenance dose of prednisone. In three cases of pemphigus vulgaris and one case of pemphigus foliaceus, dexamethasone and cyclophosphamide pulse therapy associated with prednisone helped the lesions to heal more rapidly. Neither treatment however prevented the recurrence of the disease. Amenorrhea, myelotoxicity and Stevens-Johnson syndrome were among the cyclophosphamide side effects. All the patients treated with prednisone experienced known side effects.

Alopecia areata treated with phenolisation and intravenous dexamethasone pulses

Phenol is an aromatic hydrocarbon derived from coal tar or manufactured from monochlorobenzene. Alopecia areata is a common non scarring autoimmune condition characterised by patchy loss of hair without atrophy. Various treatment modalities have been proposed and used for the treatment of alopecia areata, which is indeed a difficult condition to treat. Variable results have been documented using intralesional corticosteroid injections, topical minoxidil, topical anthralin ointment, topical contact sensitizers like diphencyprone, dinitrochlorobenzene or squaric acid dibutyl ester, and oral mini pulse with betamethasone. The use of 88% phenol for the treatment of alopecia areata has been documented in literature, but it has failed to secure a place in the priority list. Herein we have reported a case of a young girl who was treated with short-time aggressive therapy using 88% phenol and dexamethasone pulse therapy and who responded well to the treatment with no recurrence in the last 6 months of follow-up.