Cardiopulmonary rehabilitation programme improves physical health and quality of life in post-COVID syndrome.

BACKGROUND: Many patients with previous COVID-19 infection suffer from prolonged symptoms after their recovery: cough, dyspnea, chest pain, shortness of breath, fatigue, anxiety or depression, regardless of milder or severe coronavirus infection. Review of the literature demonstrates underrepresented complex cardiopulmonary rehabilitation of patients with post-COVID syndrome. The aim of our quasi-experimental study was to evaluate the effectiveness of complex cardiopulmonary rehabilitation and to assess the quality of life, functional parameters before and after a 14-day specific cardiopulmonary rehabilitation and two months later. METHODS: Sixty-eight patients participated in rehabilitation at Semmelweis University's Department of Pulmonology. Respiratory function: forced expiratory volume in 1 second (FEV1%pred), 6-minute walk test (6MWT), chest kinematics (CK), quality of life [EuroQol-5D (EQ-5D), Post-COVID-19 Functional Status (PCFS)] and Modified Medical Research Council (mMRC) dyspnea scale were measured at the beginning and end of the programme and two months after the rehabilitation. RESULTS: The 14-day rehabilitation programme resulted in significant improvement of 6MWT {492 [interquartile range (IQR), 435-547] vs. 523 (IQR, 477-580) m; P=0.031}, mMRC [1 (IQR, 0.25-1) vs. 0 (IQR, 0-1); P=0.003], EQ-VAS score [75 (IQR, 65-80) vs. 85 (IQR, 75-90); P=0.015], and PCFS [1 (IQR, 1-2) vs. 0.5 (IQR, 0-1); P=0.032]. Respiratory function and chest kinematics also improved, FEV1(%pred) [86 (IQR, 73-103) vs. 91 (IQR, 80-99); P=0.360], chest kinematics [3.5 (IQR, 2.75-4.25) vs. 4 (IQR, 1-5.25) cm; P=0.296], and breath-holding test (BHT) [33 (IQR, 23-44) vs. 41 (IQR, 28-58) s; P=0.041]. CONCLUSIONS: Complex cardiopulmonary rehabilitation improved workload, quality of life, respiratory function, complaints and clinical status of patients with post-COVID syndrome. Personalized complex pulmonary rehabilitation can be beneficial and recommended for patients suffer from post-COVID syndrome, who have good potential for recovery and are able to participate in the two weeks complex pulmonary rehabilitation.

Fatigue, sleepiness and sleep quality are SARS-CoV-2 variant independent in patients with long COVID symptoms.

Acute infections with SARS-CoV-2 variants of concerns (VOCs) differ in clinical presentation. Discrepancies in their long-term sequelae, commonly referred to as long COVID, however, remain to be explored. We retrospectively analyzed data of 287 patients presented at the post-COVID care of the Pulmonology Department, Semmelweis University, Budapest, Hungary, and infected with SARS-CoV-2 during a period of 3 major epidemic waves in Hungary (February-July 2021, VOC: B.1.1.7, Alpha, N = 135; August-December 2021, VOC: B.1.617.2, Delta, N = 89; and January-June 2022, VOC: B.1.1.529, Omicron; N = 63), > 4 weeks after acute COVID-19. Overall, the ratio of long COVID symptomatic (LC) and asymptomatic (NS) patients was 2:1. Self-reported questionnaires on fatigue (Fatigue Severity Scale, FSS), sleepiness (Epworth Sleepiness Scale, ESS) and sleep quality (Pittsburgh Sleep Quality Index, PSQI) showed higher scores for LC (4.79 ± 0.12, 7.45 ± 0.33 and 7.46 ± 0.27, respectively) than NS patients (2.85 ± 0.16, 5.23 ± 0.32 and 4.26 ± 0.29, respectively; p < 0.05 for all vs. LC). By comparing data of the three waves, mean FSS and PSQI scores of LC patients, but not ESS scores, exceeded the normal range in all, with no significant inter-wave differences. Considering FSS ≥ 4 and PSQI > 5 cutoff values, LC patients commonly exhibited problematic fatigue (≥ 70%) and poor sleep quality (> 60%) in all three waves. Comparative analysis of PSQI component scores of LC patients identified no significant differences between the three waves. Our findings highlight the importance of concerted efforts to manage both fatigue and sleep disturbances in long COVID patient care. This multifaceted approach should be followed in all cases infected with either VOCs of SARS-CoV-2.

Lung Transplant Rehabilitation-A Review.

BACKGROUND: Both lung transplant recipients and candidates are characterised by reduced training capacity and low average quality of life (QoL). This review investigates the impact of training on exercise ability and QoL in patients before and after lung transplant. METHODS: Searches were conducted from the beginning to 7 March 2022 using the terms "exercise," "rehabilitation," "lung transplant," "exercise ability," "survival," "quality of life" and "telerehabilitation" in six databases, including Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, CINAHL, Nursing and Allied Health, and Scopus. The inclusion criteria were studies evaluating the effects of an exercise training programme concurrent with lung transplantation as well as patients and candidates (>18 years old) through any lung diseases. The term "lung transplant rehabilitation" was used to refer to all carefully thought-out physical activities with the ultimate or intermediate objective of improving or maintaining physical health. RESULTS: Out of 1422 articles, 10 clinical- and 3 telerehabilitation studies, candidates (n = 420) and recipients (n = 116) were related to the criteria and included in this review. The main outcome significantly improved in all studies. The 6-min walk distance, maximum exercise capacity, peak oxygen uptake, or endurance for constant load rate cycling improved measuring physical activity [aerobic exercises, breathing training, and aerobic and inspiratory muscle training sessions (IMT)]. Overall scores for dyspnoea improved after exercise training. Furthermore, health-related quality of life (HRQOL) also improved after aerobic exercise training, which was performed unsupervised or accompanied by breathing sessions. Aerobic training alone rather than combined with inspiratory muscle- (IMT) or breathing training enhanced exercise capacity. CONCLUSION: In conclusion, rehabilitation programmes seem to be beneficial to patients both preceding and following lung transplantation. More studies are required to determine the best training settings in terms of time scale, frequency, and work intensity in terms of improving exercise ability, dyspnoea, and HRQOL.

Serological findings following the second and third SARS-CoV-2 vaccines in lung transplant recipients.

INTRODUCTION: Lung transplant recipients (LuTX) represent a vulnerable population for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though many vaccines are already developed, more clinical data need to support effective immunological response in immunocompromised patients. METHODS: Stable LuTX recipients with no medical history of coronavirus disease (COVID-19) were enrolled. Currently available messenger RNA (mRNA) (BNT162b2-mRNA, mRNA-1273) and non-mRNA (ChAdOx1, BBIBP-CorV) vaccines were given according to availability, boosters were all mRNA-based. SARS-CoV-2 Spike1 immunoglobulin G (IgG) antibody titer was evaluated before and 2 weeks after second and third dose. Difference between mRNA versus non-mRNA vaccines was assessed. RESULTS: Forty-one patients (49% men, age 48.4 ± 13.8 years) received two doses of SARS-CoV-2 vaccines: 23 of mRNA, 18 of non-mRNA, and 24/41 (58%) received a third dose. Median 92 months passed since transplantation, and serum level of tacrolimus was median 5.5 ng/ml. Positive serology was found in 37% of all patients after the second dose, 86% had mRNA vaccine. After the third dose, 29% became positive who had no antibody before. Significantly higher level of antibody was found after the second mRNA than non-mRNA vaccines (2.2 vs. 1568.8 U/ml, respectively, p = .002). 6/23 (26%) patients received two doses of mRNA vaccine developed COVID-19 after the second injection in an average of 178 days, half of them recovered, half of them died in intensive care unit (ICU). 3/6 (50%) patients with two doses mRNA and recovered from COVID-19 had significantly higher level of antibody (average 20847.3 U/ml) than without infection. After the booster vaccine, 1/24 (4%) developed infection. CONCLUSION: Immunosuppression therapy may induce a weaker SARS-CoV-2 response in LuTX recipients; therefore, third dose is a priority in transplanted patients. The highest antibody level was measured recovering from COVID after two doses. Our data confirm that booster mRNA vaccine could increase antibody levels, even if immunization was started with non-mRNA vaccine.

Peripheral blood and bronchoalveolar leukocyte profile in lung transplant recipients and their changes according to immunosuppressive regimen: A single-center experience.

BACKGROUND: After lung transplantation (LuTX), lower respiratory tract infections (LRTI) and acute cellular rejection (ACR) are associated with changes in peripheral blood and bronchoalveolar lavage fluid mononuclear cell profile (PBMC and BALIC). PBMC is also influenced by immunosuppressive regimen and its changes with postoperative time. First-year PBMC and BALIC changes were evaluated in this study with rabbit anti-thymocyte globulin (ATG) and alemtuzumab (AL) induction therapy. METHODS: In total, 64 LuTX recipients were included, 53 of them received AL and 11 ATG as induction therapy. PBMC and BALIC were examined routinely and in cases suspicious of infection and/or rejection. A PBMC- and BALIC-based algorithm for infection and rejection prediction was also tested. RESULTS: In the AL group, peripheral blood lymphocyte and basophil cell numbers were significantly reduced, while the neutrophil cell number elevation during LRTI was significantly higher compared to the control. Early postoperative measurements showed a lower BALIC lymphocyte count. The algorithm had 17% sensitivity and 94% specificity for ACR in all patients and 33% sensitivity and 95% specificity for ACR with coexisting LRTI. CONCLUSION: BALIC is not significantly influenced by the immunosuppressive regimen. PBMC- and BALIC-based algorithm may improve the differential diagnosis of ACR.

Outpatient rehabilitation programs for COVID-19 patients / Ambuláns rehabilitációs programok COVID-19-betegek számára.

Összefoglaló. A COVID-19-fertozésen átesett betegek közül többen elhúzódó panaszokról számolnak be a felépülést követoen, sokaknál tartósan fennáll a köhögés, a nehézlégzés, a mellkasi fájdalom, a légszomj attól függetlenül, hogy enyhe vagy súlyosabb tüneteket okozott a koronavírus. A betegek erotlennek érzik magukat, eros fáradtságérzetre panaszkodnak, míg mások gyomor-bél rendszeri panaszokra, fejfájásra, depresszióra, a szaglás- és ízérzékelés elvesztésére. Számtalan kutatás leírja, hogy a fertozés még akár hónapokkal késobb is hatással lehet a tüdo muködésére, és korábban egészséges tüdon is látható a koronavírus-fertozés a gyógyulás után három hónappal készült kontroll-mellkas-CT-leleten. Éppen ezért szükség van a fertozés lezajlását követoen tüdogyógyászati kivizsgálásra, ha a betegnek elhúzódó panaszai vannak, vagy ha a betegség tüdogyulladást okozott. Szükség van a jelenleg muködo fekvobeteg-légzoszervi rehabilitáció mellett a kezelés ambuláns kiterjesztésére is, melynek célja újabb kórházi ápolás nélkül a teljes gyógyulás elérése a betegeknél. A COVID-19-fertozésen átesett betegeknél a komplex rehabilitáció hatására javul a terhelhetoség, az életminoség, javulnak a légzésfunkciós értékek, csökkennek a panaszok, javul a betegek fizikai és pszichikai állapota. Összefoglaló kutatásunk célja áttekinteni, hogy milyen COVID-19 ambuláns rehabilitációs programok indultak el a koronavírus-fertozésen átesett betegek esetében nemzetközi és hazai színtereken. Orv Hetil. 22021; 162(42): 1671-1677. Summary. Several patients with COVID-19 infection report prolonged complaints after recovery and many of them suffer from persistent cough, dyspnea, chest pain and shortness of breath regardless of whether the coronavirus caused mild or more severe symptoms. They complain of severe fatigue and weakness while others grizzle about gastrointestinal complaints, headache, depression, loss of sense of smell and taste. Numerous studies describe that the infection can affect lung function even in months and coronavirus infection can be detectable in previously healthy lungs by taking a control chest CT scan three months after recovery. Therefore, chest follow-up is required after the infection if the patient has prolonged complaints or if the disease has caused pneumonia. In addition to the currently operating inpatient respiratory rehabilitation, there is also a need for an outpatient extension of treatment to achieve complete recovery in patients without further hospitalization. For those patients who have had the COVID-19 infection complex rehabilitation can improve their workload, quality of life, improves their respiratory function values, reduces their complaints and also improves their physical and mental condition. The aim of our summary research is to review what COVID-19 outpatient rehabilitation programs have been initiated for patients who went through coronavirus infection on international and domestic scenes. Orv Hetil. 2021; 162(42): 1671-1677.

The effectiveness of pulmonary rehabilitation in connection with lung transplantation in Hungary.

BACKGROUND: The role of pre- and post-lung transplant rehabilitation is to maintain or improve exercise tolerance, lung mechanics, peripheral and respiratory muscle function. Our aim was to measure the effectiveness of pre- and post-transplant rehabilitation in terms of the changes of functional and quality of life markers. METHODS: Sixty-three patients (40 COPD FEV1: 21±5%pred, 18 IPF TLC: 42±13%pred, 4 bronchiectasis FEV1: 28±4%pred and 1 alveolitis fibrotisans TLC: 31%pred) participated in a pre- and 14 took part in a post-transplant rehabilitation program (more than 2 months after lung transplantation (LTx), primary diagnoses: 9 COPD, 4 IPF). The rehabilitation program consisted of chest-wall stretching, controlled breathing techniques and personalized exercise of 20-30 minutes by cycling and treadmill 2-3 times per day for 4 weeks. Seven functional and quality of life markers, like lung function, chest wall expansion (CWE), 6-minute walking distance (6MWD), modified Medical Research Council Dyspnea Scale (mMRC), COPD Assessment Test (CAT), breath holding time (BHT) and hand grip strength (HGS) were measured at the onset and the end of the rehabilitation program. The safety profile of the rehabilitation program was followed-up. RESULTS: Pre-transplant pulmonary rehabilitation resulted in significant improvement in CWE (3.24±1.49 vs. 4.48±1.62 cm), CAT IQR {19 [13-25] vs. 15 [11-21]}, 6MWD (315±118 vs. 375±114 m), P<0.05. FEV1, FVC, mMRC, BHT and HGS did not change significantly. Post-transplant rehabilitation resulted in significant improvement in CWE (3.7±2.1 vs. 6.2±1.8 cm), CAT IQR {17 [11-23] vs. 10 [6-14], BHT (22±14 vs. 35±16 s), FEV1 (73±8 vs. 86±9%pred) and FVC (70±12 vs. 85±14%pred), P<0.05. The 6MWD, mMRC and HGS did not change significantly. No cardiovascular or other side effects were detected during the rehabilitation program. CONCLUSIONS: Our results underline the importance of perioperative pulmonary rehabilitation in the complex treatment of lung transplant patients in Hungary, as well. There was a limitation because no control group was evaluated without rehabilitation.

Lung Function Changes are More Common in Marfan Patients Who Need Major Thoracic Surgery.

INTRODUCTION: Marfan syndrome is a genetic disorder affecting the connective tissue. Changes in lung tissue might influence respiratory function; however, a detailed respiratory functional assessment according to the need for major thoracic surgery is missing. METHODS: Comprehensive pulmonary examinations were performed in 55 Marfan patients including respiratory symptoms, lung function (LF) testing using European Coal and Steel Community (ECSC) reference values, TLCO and quality of life measurements. Groups included patients who did not need surgery (Mf, n = 32) and those who underwent major thoracic surgery (Mfop, n = 23). RESULTS: Respiratory symptoms affected 20% of patients. Scoliosis was significantly more frequent in the Mfop group. LF demonstrated in all Marfan patients a tendency towards airway obstruction (FEV1/FVC = 0.77 ± 0.10), more prominent in Mfop patients (0.74 ± 0.08 vs. Mf: 0.80 ± 0.11; p = 0.03). Correction of LF values using a standing height modification by arm span (Hcorrected) revealed additional changes in FVC and FEV1. TLCO and quality of life did not differ between groups. CONCLUSIONS: Marfan syndrome is associated with airway obstruction, especially in patients who have undergone major thoracic surgery, indicative of more severe connective tissue malfunction. The use of arm span for height correction is suitable to evaluate LF changes in this special patient group including patients with significant scoliosis.

Seasonal changes of lower respiratory tract infections in lung transplant recipients during the first post-transplant year: The Hungarian experience.

BACKGROUND: After lung transplantation (LuTX) a high level of immunosuppression is needed to prevent rejection of the graft. Together with earlier colonization by pathogens, immunosuppression makes recipients more susceptible to infections, especially during the first postoperative year. As seasonality of lower respiratory tract infections (LRTI) is well-known in chronic lung diseases, we assessed seasonal changes of pathogen spectrum and number of infections in the first postoperative year in LuTX recipients. METHODS: LRTI were analyzed in 28 Hungarian adult LuTX patients. Incidence and spectrum of microorganism causing LRTI were evaluated according to post-transplant time and seasonal temperature and humidity changes. RESULTS: A total of 69 cases of LRTI were registered (average: 1.9 cases/patient; range: 0-14). Gram-negative=59, gram-positive=26, and fungal=31 pathogens were detected, with polymicrobial samples in 46% of all cases. Increased number of LRTI was observed in the cold season (1.68±1.54 vs 0.79±0.92 case/month/patient, P<.01) and significant negative correlations were identified between the incidence of polymicrobial and bacterial infections and temperature (r2 =0.1535, P<.05, r2 =0.3144, P<.01, respectively). In addition, positive correlation was observed between polymicrobial infections and humidity (r2 =0.1403, P<.05). Higher incidence of LRTI was also noted in the cold season, when accounting for the differences in immunosuppression. CONCLUSION: Seasons influenced the incidence of LRTI in the first postoperative year in LuTX recipients. More intensive vigilance for possible gram-negative and polymicrobial infections is needed in these patients in cold and wet seasons in the continental climate zone, regardless of underlying disease.

Characteristics of reversible and nonreversible COPD and asthma and COPD overlap syndrome patients: an analysis of salbutamol Easyhaler data.

The choice of inhaler device for bronchodilator reversibility is crucial since suboptimal inhalation technique may influence the result. On the other hand, bronchodilator response also varies from time to time and may depend on patient characteristics. In this study, patients with airway obstruction (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] ratio <70% in chronic obstructive pulmonary disease [COPD]; <80% in asthma) were included (n=121, age: 57.8±17.3 years). Bronchodilator reversibility (American Thoracic Society/European Respiratory Society criteria) was tested in patients with COPD (n=63) and asthma and COPD overlap syndrome (ACOS; n=12). Forty-six asthmatics served as controls. Reversibility was tested with 400 µg salbutamol dry powder inhaler (Buventol Easyhaler, Orion Pharma Ltd, Espoo, Finland). Demographic data and patients' perceptions of Easyhaler compared with ß2-agonist pressurized metered dose inhalers (pMDIs) were analyzed. American Thoracic Society/European Respiratory Society guideline defined reversibility was found in 21 out of 63 COPD patients and in two out of 12 ACOS patients. Airway obstruction was more severe in COPD patients as compared with controls (mean FEV1 and FEV1% predicted both P<0.0001). Average response to salbutamol was significantly lower in COPD patients compared with asthma controls (P<0.0001). Reversibility was equally often found in smokers as in never-smokers (33% vs 34%). Nonreversible COPD patients had higher mean weight, body mass index, and FEV1/FVC compared with reversible COPD patients. Most patients preferred Easyhaler and defined its use as simpler and more effective than use of a pMDI. Never-smokers and patients with asthma experienced Easy-haler somewhat easier to use than smokers and patients with COPD. In conclusion, a substantial part of patients with COPD or ACOS showed reversibility to salbutamol dry powder inhaler. Nonreversible patients with COPD were characterized by higher weight and body mass index, and a higher FEV1/FVC ratio. Most patients preferred Easyhaler compared with a pMDI.

Peripheral CD4+ cell prevalence and pleuropulmonary manifestations in systemic lupus erythematosus patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease involving several organs, including the lungs. Previous results confirmed changes of peripheral T cell subsets in lupus patients; however no data are available about their possible relationship with pulmonary involvement. OBJECTIVE: To determine pulmonary manifestations and potential relationship in changes of peripheral CD4+ T cell subsets. METHODS: Patients with SLE (N = 28) were enrolled in complex pulmonary examination. Patients were divided into groups with pleuropulmonary manifestations (SLEpulm N = 13 age: 44.9 ± 3.3 years, female: male = 11:2) or without (SLEc N = 15 age: 27.2 ± 3.7 years, female: male = 12:3). Peripheral blood was taken for T helper (Th)1, Th2, Th17, CD4+CD25hi+ and regulatory T (Treg: CD4+CD25hi+ CD127-) cell analysis from SLE patients and healthy volunteers (controls, N = 40). RESULTS: SLEpulm patients were older, had more pulmonary symptoms and significantly decreased pO2 as compared to SLEc group. Ventilatory disorder was present in 92% of SLEpulm patients, with significantly decreased lung volumes, signs of airway involvement and decrease in DLco. Significant increase in Th1/Th2, while decrease in Th17/Treg ratios was present in all SLE compared to controls. In SLEpulm CD4+CD25hi+ subset without changes in Treg number was significantly increased as compared to SLEc and this subgroup of T cell showed significant positive correlation with dynamic lung function parameters and DLco (p < 0.05). CONCLUSION: In lupus patients pleuropulmonary manifestations are prevalent and lung function and blood gas measurements should be regularly performed in the daily clinical assessment. Significant increase of activated CD4+CD25hi+ T cells, but not Treg is associated with decreased lung function parameters in SLEpulm patients.

[Pulmonary infections following solid organ transplantation]. / Szervtranszplantációt kíséro pulmonalis infekciók.

Solid organ transplantation is the standard of care for selected patients with severe vital organ dysfunction. The need for immunosuppression to prevent organ rejection is a common characteristic of recipients. Immunosuppression increases the risk of infections, especially with low virulence opportunistic pathogens. Infections following solid organ transplantation mainly affect the lungs and the airways. Establishing the diagnosis includes a wide spectrum of pulmonary diagnostics, high standard microbiological analysis and various imaging methods. With the improvement of treatment options, the number of kidney, liver, heart and lung transplant recipients is increasing and, therefore, more and more physicians may meet pulmonary complications in these patients.

Tumor cell expression of heat shock protein (HSP) 72 is influenced by HSP72 [HSPA1B A(1267)G] polymorphism and predicts survival in small Cell lung cancer (SCLC) patients.

The inducible heat shock protein (HSP)72 plays a central role in antitumor immunomodulation. HSP72 expression was assessed on tumor samples of 43 patients with advanced and metastatic small cell lung cancer (SCLC) by immunohistochemistry and HSP72 [HSPA1B A(1267)G] polymorphism was determined. HSP72 expression of SCLC cells was significantly decreased in GG as compared to cells of AA or AG genotype patients, and was associated with significantly shorter survival in GG patients as compared to carriers of the A allele. Decreased HSP72 expression of SCLC cells associated with HSP72 GG genotype is a negative prognostic factor for survival in SCLC patients.

Static and dynamic changes in carotid artery diameter in humans during and after strenuous exercise.

Arterial baroreflex function is altered by dynamic exercise, but it is not clear to what extent baroreflex changes are due to altered transduction of pressure into deformation of the barosensory vessel wall. In this study we measured changes in mean common carotid artery diameter and the pulsatile pressure : diameter ratio (PDR) during and after dynamic exercise. Ten young, healthy subjects performed a graded exercise protocol to exhaustion on a bicycle ergometer. Carotid dimensions were measured with an ultrasound wall-tracking system; central arterial pressure was measured with the use of radial tonometry and the generalized transfer function; baroreflex sensitivity (BRS) was assessed in the post-exercise period by spectral analysis and the sequence method. Data are given as means +/- S.E.M. Mean carotid artery diameter increased during exercise as compared with control levels, but carotid distension amplitude did not change. PDR was reduced from 27.3+/-2.7 to 13.7+/-1.0 microm mmHg(-1). Immediately after stopping exercise, the carotid artery constricted and PDR remained reduced. At 60 min post-exercise, the carotid artery dilated and the PDR increased above control levels (33.9+/-1.4 microm mmHg(-1)). The post-exercise changes in PDR were closely paralleled by those in BRS (0.74< or = r < or =0.83, P<0.05). These changes in mean carotid diameter and PDR suggest that the mean baroreceptor activity level increases during exercise, with reduced dynamic sensitivity; at the end of exercise baroreceptors are suddenly unloaded, then at 1 h post-exercise, baroreceptor activity increases again with increasing dynamic sensitivity. The close correlation between PDR and BRS observed at post-exercise underlies the significance of mechanical factors in arterial baroreflex control.