Long-Term Follow-Up of Patients Needing Extracorporeal Membrane Oxygenation Following a Critical Course of COVID-19.

INTRODUCTION: Severe respiratory failure is one of the most serious complications of coronavirus disease 2019 (COVID-19). In a small proportion of patients, mechanical ventilation fails to provide adequate oxygenation and extracorporeal membrane oxygenation (ECMO) is needed. The surviving individuals need long-term follow-up as it is not clear what their prognosis is. AIM: To provide a complex clinical picture of patients during follow-up exceeding one year after the ECMO therapy due to severe COVID-19. METHODS: All subjects involved in the study required ECMO in the acute stage of COVID-19. The survivors were followed-up for over one year at a specialized respiratory medical center. RESULTS: Of the 41 patients indicated for ECMO, 17 patients (64.7% males) survived. The average age of survivors was 47.8 years, and the average BMI was 34.7 kg·m-2. The duration of ECMO support was 9.4 days. A mild decrease in vital capacity (VC) and transfer factor (DLCO) was observed on the initial follow-up visit (82.1% and 60%, respectively). VC improved by 6.2% and by an additional 7.5% after 6 months and 1 year, respectively. DLCO improved by 21.1% after 6 months and remained stable after 1 year. Post-intensive care consequences included psychological problems and neurological impairment in 29% of patients; 64.7% of the survivors got vaccinated against SARS-CoV-2 within 12 months of hospitalization and 17.6% experienced reinfection with a mild course. CONCLUSION: The COVID-19 pandemic has significantly increased the need for ECMO. Patients' quality of life after ECMO is temporarily significantly reduced but most patients do not experience permanent disability.

One year health-related quality of life after discharge: a prospective cohort study among COVID-19 ICU survivors

Considering the paucity of data on long-term Health-Related Quality of Life (HRQoL) in coronavirus disease 2019 (COVID-19) intensive care unit (ICU) survivors, we present one-year follow-up results on patients' HRQoL and compare them with those of the already reported 6-month follow-up. We conducted a prospective cohort study of patients in COVID-19 ICU between March and June 2020. A HRQoL analysis was performed six months and 1 year after discharge by means of a short-form-36 (SF-36) questionnaire. Hospital mortality in 403 ICU COVID-19 patients was 44.9%;further 4.0% died between hospital discharge and 6-month follow-up and only 0.5% died in the next six months. The median physical component of HRQoL increased from 43.7 (interquartile range (IQR): 31.7-52.7) at 6 months to 46.0 (IQR: 38.0-53.0) 1 year after hospital discharge (p = 0.007). In multivariable regression analysis, age >50 (odds ratio (OR) 0.270) and female sex (OR 0.144) were independently associated with reduced physical HRQoL 1 year after discharge. The median mental component of HRQoL increased from 50.6 (IQR: 42.0-55.8) at 6 months to 53.0 (IQR: 47.0-56.0) 1 year after discharge (p = 0.035), with no significant predictors. Increased HRQoL was associated with an improvement in patients' physical status, role functioning, emotional well-being (all p < 0.001) and social functioning (p = 0.007). ICU COVID-19 patients' HRQoL slightly improved 1 year after discharge, when compared to results of the 6-month follow-up. Medications received during ICU stay had no effect on physical or mental HRQoL.Copyright © 2023 The Author(s). Published by MRE Press.

The use of extracorporeal membrane oxygenation in the treatment of critical course of pneumonia

Extracorporeal membrane oxygenation is the highest form of resuscitation care in management of patients with respiratory failure. In the case of acute respiratory distress syndrome, the veno-venous setting is more often used. ECMO support enables, in case of lung function failure, to obtain the necessary time for the onset of the causal treatment effect or is used as a bridge to transplantation Mortality of the patients varies according to the underlying cause and presence of risk factors (e.g., age, complications or comorbid diseases). The onset of the COVID-19 pandemic has led to a significant increase in the need for ECMO. The quality of life of patients after ECMO is significantly reduced, but most patients do not experience permanent disability. © 2022, Czech Medical Association J.E. Purkyne. All rights reserved.

The use of extracorporeal membrane oxygenation in the treatment of critical course of pneumonia.

Extracorporeal membrane oxygenation is the highest form of resuscitation care in management of patients with respiratory failure. In the case of acute respiratory distress syndrome, the veno-venous setting is more often used. ECMO support enables, in case of lung function failure, to obtain the necessary time for the onset of the causal treatment effect or is used as a bridge to transplantation Mortality of the patients varies according to the underlying cause and presence of risk factors (e.g., age, complications or comorbid diseases). The onset of the COVID-19 pandemic has led to a significant increase in the need for ECMO. The quality of life of patients after ECMO is significantly reduced, but most patients do not experience permanent disability.

Poor long-term recovery after critical COVID-19 during 12 months longitudinal follow-up.

OBJECTIVES: This study aimed to describe the burden of illness and impact on health and working situation among former intensive care patients treated for COVID-19. METHODS: A prospective cohort study was performed at one intensive care unit of a university hospital in Sweden during the first wave of COVID-19 in spring 2020. The burden of illness in health status, cognitive, physical, and psychological outcomes, and working situation were assessed at four and 12 months after discharge from intensive care, using nine validated instruments. RESULTS: Forty-six participants treated for COVID-19 participated in both follow-ups and were included in this study. General fatigue was reported by 37 of 46 participants (82%) at both follow-ups (p = 1.000). For overall health status 28 (61%) participants at the first follow-up and 26 (57%) (p = 0.414) at the second reported lower values than the general population. Cognitive impairment was seen in 22 (52%) participants at four months and in 13 (31%) at 12 months (p = 0.029). The proportion of participants on sick-leave decreased between the first and second follow-up (24% vs 13%, p = 0.025), but the proportion of participants working full-time was almost the same at both follow-ups (35% vs 37%, p = 0.317). CONCLUSIONS: The burden of illness of patients treated in intensive care due to COVID-19 included cognitive, physical, and psychological impacts. Cognitive functions were improved after 12 months, but no clear improvements could be distinguished in the physical or psychological outcome. Higher burden of illness was associated with inability to return to work.

Four Months Physical, Psychosocial, and Neurocognitive Follow-up of Multisystemic Inflammatory Syndrome in Children (Mis-C) after Picu Admission: A National Prospective Cohort Study

BACKGROUND AND AIM: Outcome of the novel COVID-19 related disease "Multisystemic Inflammatory Syndrome in Children (MIS-C)" is still largely unknown. We aimed to assess physical, psychosocial, and neurocognitive functioning in MIS-C survivors after PICU admission. METHOD(S): A national prospective cohort study including MIS-C children (0-17 years) admitted to one of the 7 PICUs in The Netherlands. Children were tested 3-6 months after PICU admission in a multidisciplinary follow-up program through a semi-structured interview, validated questionnaires for psychosocial outcomes, in both children and their parents, and validated neurocognitive tests in children. RESULT(S): Between March 2020 and June 2021, 49 MIS-C children attended follow-up after median 4 months (IQR 3-5) at median age 11.6 years (IQR 9.3-15.6). At follow-up, PCPC and POPC scores were normal in all children, 21 (43%) children reported impaired exercise intolerance and 20% worsening sleeping behaviour. Physical and school functioning quality of life scores were worse compared with norm data. General intelligence and verbal memory scores were comparable to norm data (N=44), whereas visual memory, sustained attention, and planning were significantly lower in a subgroup of 29 patients. Parents reported less posttraumatic stress and depressive symptoms compared with norms. CONCLUSION(S): After PICU admission, exercise intolerance, sleeping, physical and school functioning problems were reported. Overall intelligence and neurocognitive scores were normal, with subtle deviants in some neurocognitive functions indicating integration and sustained attention problems. This yields for a longer-term follow-up to assess MIS-C survivors functioning.

LPS versus Poly I:C model: comparison of long-term effects of bacterial and viral maternal immune activation on the offspring.

A prominent health issue nowadays is the COVID-19 pandemic, which poses acute risks to human health. However, the long-term health consequences are largely unknown and cannot be neglected. An especially vulnerable period for infection is pregnancy, when infections could have long-term health effect on the child. Evidence suggests that maternal immune activation (MIA) induced by either bacteria or viruses presents various effects on the offspring, leading to adverse phenotypes in many organ systems. This review compares the mechanisms of bacterial and viral MIA and the possible long-term outcomes for the offspring by summarizing the outcome in animal LPS and Poly I:C models. Both models are activated immune responses mediated by Toll-like receptors. The outcomes for MIA offspring include neurodevelopment, immune response, circulation, metabolism, and reproduction. Some of these changes continue to exist until later life. Besides different doses and batches of LPS and Poly I:C, the injection day, administration route, and also different animal species influence the outcomes. Here, we specifically aim to support colleagues when choosing their animal models for future studies.

Prospectively Assessed Long-Term Outcomes of Patients with E-Cigarette- or Vaping-associated Lung Injury.

Rationale: E-cigarette- or vaping-associated lung injury (EVALI) was first identified in 2019. The long-term respiratory, cognitive, mood disorder, and vaping behavior outcomes of patients with EVALI remain unknown. Objectives: To determine the long-term respiratory, cognitive, mood disorder, and vaping behavior outcomes of patients with EVALI. Methods: We prospectively enrolled patients with EVALI from two health systems. We assessed outcomes at 1 year after onset of EVALI using validated instruments measuring cognitive function, depression, anxiety, post-traumatic stress, respiratory disability, coronavirus disease (COVID-19) infection, pulmonary function, and vaping behaviors. We used multivariable regression to identify risk factors of post-EVALI vaping behaviors and to identify whether admission to the intensive care unit (ICU) was associated with cognitive, respiratory, or mood symptoms. Results: Seventy-three patients completed 12-month follow-up. Most patients were male (66.7%), young (mean age, 31 ± 11 yr), and White (85%) and did not need admission to the ICU (59%). At 12 months, 39% (25 of 64) had cognitive impairment, whereas 48% (30 of 62) reported respiratory limitations. Mood disorders were common, with 59% (38 of 64) reporting anxiety and/or depression and 62% (39 of 63) having post-traumatic stress. Four (6.4%) of 64 reported a history of COVID-19 infection. Despite the history of EVALI, many people continued to vape. Only 38% (24 of 64) reported quitting all vaping and smoking behaviors. Younger age was associated with reduced vaping behavior after EVALI (odds ratio, 0.93; P = 0.02). ICU admission was not associated with cognitive impairment, dyspnea, or mood symptoms. Conclusions: Patients with EVALI, despite their youth, commonly have significant long-term respiratory disability; cognitive impairment; symptoms of depression, anxiety, post-traumatic stress; and persistent vaping.

The effect of intravitreal dexamethasone implantation on diabetic macular edema refractory to anti-vascular endothelial growth factor treatment

Purpose: To evaluate the efficacy and safety of intravitreal dexamethasone (DEX) implantation for diabetic macular edema (DME) that proved unresponsive to previous anti-vascular endothelial growth factor (VEGF) treatment. Methods: This prospective interventional study recruited 91 patients with refractory DME after previous anti-VEGF treatments in one or both eyes. All patients were followed up for at least 12 months. Best-corrected visual acuity (BCVA), central subfield thickness (CST) and macular volume were measured. Results: Over the 12 months, a mean of 2.1 +/- 0.8 DEX implantations were administered per eye;26 eyes (28.9%) received 1 implantation, 31 (34.4%) received 2, and 34 (36.7%) received 3. BCVA was significantly improved in the first 6 months, from 54.8 to 59.5 letters. Both CST and macular volume decreased significantly after DEX implantation and maintained these improvements for at least 12 months. Subjects who needed the second DEX implantation had a greater number of prior anti-VEGF injections than did those who needed only one implantation (6.0 vs 3.0). Conclusions: Two-thirds of refractory DME required less than two DEX implantations to maintain a dry macula for 12 months. Early switching to intravitreal DEX can be considered as the second-line therapeutic option, especially during the COVID-19 pandemic.

Impact of COVID-19 severity on health-related quality of life among Saudi adult patients.

COVID-19 patients may experience varying degrees of symptom severity, significantly impacting the health-related quality of life. As a result, the current study examines the impact of symptom severity on health-related quality of life among Saudi adult COVID- 19 patients. In this cross-sectional study 310 adult COVID-19 patients were recruited through a snowball technique in Saudi Arabia. We used a questionnaire (SF-12 RAND tool questionnaire) that included three parts: sociodemographic factors, perception of degree severity of COVID-19 symptoms, and health-related quality of life (HRQoL). Out of 310 COVID-19 adult patients, 200 (64.5%) were female, 110 (35.5%) were between 30-49 years old. The mean scores of the HRQoL, physical components summary (PCS), and mental components summary (MCS) were 58.11±17.02, 71.32±23.72, and 44.91±17.94, respectively. Patients with very severe symptoms had the lowest HRQoL mean rank (120.39, P=0.023). There was a strong positive correlation between HRQoL and PCS (0.852) and HRQoL and MCS (0.730). However, PCS and MCS had a weak positive correlation (0.292). The severity of COVID-19 symptoms had a significant impact on HRQoL. Thus, it is essential to enhance the uptake of vaccines to decrease the risk of infections and avoid impact on quality of life.

Long-term cognitive functioning is impaired in ICU-treated COVID-19 patients: a comprehensive controlled neuropsychological study.

BACKGROUND: Cognitive impairment has emerged as a common post-acute sequela of coronavirus disease 2019 (COVID-19). We hypothesised that cognitive impairment exists in patients after COVID-19 and that it is most severe in patients admitted to the intensive care unit (ICU). METHODS: This prospective controlled cohort study of 213 participants performed at the Helsinki University Hospital and the University of Helsinki, Finland, comprised three groups of patients-ICU-treated (n = 72), ward-treated (n = 49), and home-isolated (n = 44)-with confirmed COVID-19 between March 13 and December 31, 2020, participating in a comprehensive neuropsychological evaluation six months after the acute phase. Our study included a control group with no history of COVID-19 (n = 48). Medical and demographic data were collected from electronic patient records and interviews carried out four months after the acute phase. Questionnaires filled six months after the acute phase provided information about change in cognitive functioning observed by a close informant, as well as the presence of self-reported depressive and post-traumatic symptoms. RESULTS: The groups differed (effect size η2p = 0.065, p = 0.004) in the total cognitive score, calculated from neuropsychological measures in three domains (attention, executive functions, and memory). Both ICU-treated (p = 0.011) and ward-treated patients (p = 0.005) performed worse than home-isolated patients. Among those with more than 12 years of education, ICU-treated patients performed worse in the attention domain than ward-treated patients (p = 0.021) or non-COVID controls (p = 0.045); ICU-treated male patients, in particular, were impaired in executive functions (p = 0.037). CONCLUSIONS: ICU-treated COVID-19 patients, compared to patients with less severe acute COVID-19 or non-COVID controls, showed more severe long-term cognitive impairment. Among those with more than 12 years of education, impairment existed particularly in the domains of attention and for men, of executive functions. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04864938, retrospectively registered February 9, 2021.

Insomnia affects patient-reported outcome in sleep apnea treated with hypoglossal nerve stimulation.

Objective: Comorbid insomnia may impact outcomes of patients with obstructive sleep apnea (OSA) receiving hypoglossal nerve stimulation with respiratory sensing (HNS) therapy. To examine whether the presence of insomnia measured using the Insomnia Severity Index (ISI) is associated with patient-reported outcomes and objective OSA measures in patients receiving HNS therapy. Methods: In this retrospective chart review, patients with an HNS implant and ISI score at follow-up assessment were categorized as having moderate/severe insomnia or no/subthreshold insomnia. OSA-related data (Apnea Hypopnea Index, AHI; Oxygen Desaturation Index, ODI), Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), and overall patient satisfaction was compared between these patient categories. Correlations between ISI scores and each of these variables were examined. Results: Of the 132 patients, 26% had moderate/severe insomnia at follow-up assessment. ESS and FOSQ scores were worse in the insomnia group at baseline, follow-up, and in the change from baseline, but AHI and ODI scores did not differ between patients with and without insomnia. Frequency of overall satisfaction at follow-up was lower in the insomnia group (58.8% vs. 92.8% with no insomnia, P < .001). Patients with insomnia were more likely to have depression (56% vs. 27% without insomnia, P < .002). Conclusions: Insomnia is associated with worse patient-reported outcomes of daytime sleepiness and sleep-related quality of life in patients with OSA receiving HNS therapy. Depression is more prevalent in patients with comorbid insomnia. The ISI may help physicians to address comorbid insomnia and achieve high patient satisfaction and adherence to HNS therapy. Level of Evidence: 4.

Sex-Related Differences in Long-COVID-19 Syndrome.

Background: Sex differences have been demonstrated in the acute phase of coronavirus disease 2019 (COVID-19). Women (F) were found to be less prone to develop a severe disease than men (M), but few studies have assessed sex-differences in Long-COVID-19 syndrome. Methods: The aim of this prospective/retrospective study was to characterize the long-term consequences of this infection based on sex. For this purpose, we enrolled 223 patients (89 F and 134 M) who were infected by SARS-CoV-2. In the acute phase of the illness, F reported the following symptoms more frequently than M: weakness, dysgeusia, anosmia, thoracic pain, palpitations, diarrhea, and myalgia-all without significant differences in breathlessness, cough, and sleep disturbance. Results: After a mean follow-up time of 5 months after the acute phase, F were significantly more likely than M to report dyspnea, weakness, thoracic pain, palpitations, and sleep disturbance but not myalgia and cough. At the multivariate logistic regression, women were statistically significantly likely to experience persistent symptoms such as dyspnea, fatigue, chest pain, and palpitations. On the contrary, myalgia, cough, and sleep disturbance were not influenced by sex. Conclusion: We demonstrated that F were more symptomatic than M not only in the acute phase but also at follow-up. Sex was found to be an important determinant of Long-COVID-19 syndrome because it is a significant predictor of persistent symptoms in F, such as dyspnea, fatigue, chest pain, and palpitations. Our results suggest the need for long-term follow-up of these patients from a sex perspective to implement early preventive and personalized therapeutic strategies.

Long-Term Prognostic Impact of Right Ventricular Dysfunction in Patients with COVID-19.

The characteristics and clinical course of hospitalized patients with coronavirus disease 2019 (COVID-19) have been widely described, while long-term data are still poor. The aim of this study was to evaluate the long-term clinical outcome and its association with right ventricular (RV) dysfunction in hospitalized patients with COVID-19. This was a prospective multicenter study of consecutive COVID-19 patients hospitalized at seven Italian Hospitals from 28 February to 20 April 2020. The study population was divided into two groups according to echocardiographic evidence of RV dysfunction. The primary study outcome was 1-year mortality. The propensity score matching was performed to balance for potential baseline confounders. The study population consisted of 224 patients (mean age 69 ± 14, male sex 62%); RV dysfunction was diagnosed in 63 cases (28%). Patients with RV dysfunction were older (75 vs. 67 years, p < 0.001), had higher prevenance of coronary artery disease (27% vs. 11%, p = 0.003), and lower left ventricular ejection fraction (50% vs. 55%, p < 0.001). The rate of 1-year mortality (67% vs. 28%; p ≤ 0.001) was significantly higher in patients with RV dysfunction compared with patients without. After propensity score matching, patients with RV dysfunction showed a worse long-term survival (62% vs. 29%, p < 0.001). The multivariable Cox regression model showed an independent association of RV dysfunction with 1-year mortality. RV dysfunction is a relatively common finding in hospitalized COVID-19 patients, and it is independently associated with an increased risk of 1-year mortality.

Does the initial chest radiograph severity in COVID-19 impact the short- and long-term outcome? - a perspective from India.

PURPOSE: The chest radiograph (CXR) is among the most widely used investigations in coronavirus disease 2019 (COVID-19) patients. Little is known about its predictive role on the long-term outcome. The purpose of this study was to explore its association with the short and long-term outcome in COVID-19 patients. METHODS: A total of 1530 patients were assessed for the presence, radiographic pattern and distribution of lung lesions observed on baseline chest radiographs obtained at admission. The Brixia scoring system was applied for semiquantitative assessment of lesion severity. Short-term outcome was determined by clinical severity, duration of hospitalization and mortality. The 1415 survivors in this group were assessed after 5-6 months for the presence of residual symptoms. RESULTS: About 67% patients had an abnormal baseline CXR. Bilateral involvement with a basal preponderance was observed and ground-glass opacification was the most frequent finding. The Brixia score ranged from 0 to 16, median 2, interquartile range (IQR) [0-6]. About 36% patients were symptomatic on 5-6-month follow-up, with fatigability being the commonest symptom. A good correlation was observed between the CXR score and disease severity as well as duration of hospitalization. On multivariate analysis, the CXR score was found to be a significant independent predictor of in-patient mortality as well as presence of long-term residual symptoms in survivors. CONCLUSIONS: Disease severity as seen on the chest radiograph appears to play an important role in driving the short and long-term consequences of COVID-19 and could serve as a prognostic indicator, which influences short-term management and long-term follow-up.

History of Heart Failure in Patients Hospitalized Due to COVID-19: Relevant Factor of In-Hospital Complications and All-Cause Mortality up to Six Months.

BACKGROUND: Patients with heart failure (HF) are at high risk of unfavorable courses of COVID-19. The aim of this study was to evaluate characteristics and outcomes of COVID-19 patients with HF. METHODS: Data of patients hospitalized in a tertiary hospital in Poland between March 2020 and May 2021 with laboratory-confirmed COVID-19 were analyzed. The study population was divided into a HF group (patients with a history of HF) and a non-HF group. RESULTS: Out of 2184 patients (65 ± 13 years old, 50% male), 12% had a history of HF. Patients from the HF group were older, more often males, had more comorbidities, more often dyspnea, pulmonary and peripheral congestion, inflammation, and end-organ damage biomarkers. HF patients had longer and more complicated hospital stay, with more frequent acute HF development as compared with non-HF. They had significantly higher mortality assessed in hospital (35% vs. 12%) at three (53% vs. 22%) and six months (72% vs. 47%). Of 76 (4%) patients who developed acute HF, 71% died during hospitalization, 79% at three, and 87% at six months. CONCLUSIONS: The history of HF identifies patients with COVID-19 who are at high risk of in-hospital complications and mortality up to six months of follow-up.

The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study.

BACKGROUND: There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months. METHODS: In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM. RESULTS: Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51-70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06-13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, - 0.19 [- 0.28 to - 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty. CONCLUSIONS: At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning. Clinical trial registration NCT04401254 May 26, 2020.

Acute and Chronic Effects of COVID-19 on the Cardiovascular System.

COVID-19 has shown significant morbidity with the involvement of multiple systems, including the cardiovascular system. Cardiovascular manifestations in the acute phase can include myocardial injury itself, myocardial infarction, venous thromboembolic events, myocarditis, Takotsubo syndrome, and different arrhythmic events. Myocardial injury defined by the rise of cardiac biomarkers in blood has been found in multiple studies with a prevalence of about 20%. Its presence is related to worse clinical outcomes and in-hospital mortality. The mechanisms of myocardial injury have been the subject of intense research but still need to be clarified. The characterization of the cardiac affectation with echocardiography and cardiac magnetic resonance has found mixed results in different studies, with a striking incidence of imaging criteria for myocarditis. Regarding post-acute and chronic follow-up results, the persistence of symptoms and imaging changes in recovered COVID-19 patients has raised concerns about the duration and the possible significance of these findings. Even though the knowledge about this disease has increased incredibly in the last year, many aspects are still unclear and warrant further research.