Feasibility of Virtual Reality Exercises at Home for Post-COVID-19 Condition: Cohort Study.

BACKGROUND: Between 30% to 76% of COVID-19 patients have persistent physical and mental symptoms, sometimes up to 9 months after acute COVID-19. Current rehabilitation is mostly focused on the physical symptoms, whereas experts have agreed on the need for a biopsychosocial approach. A novel approach such as virtual reality (VR) rehabilitation at home might benefit patients and therapists, especially considering the expected rush of patients with post-COVID-19 condition needing rehabilitation. OBJECTIVE: The aim of this study was to investigate the feasibility of self-administered VR exercises at home for post-COVID-19 condition. METHODS: This was a single-arm feasibility study in an outpatient care setting. Patients who needed physiotherapy because of post-COVID-19 condition were included as determined by the treating physiotherapist. Participants performed VR physical exercises at home for a period of 6 weeks and were allowed to perform VR mental exercise through applications available on the VR platform to reduce stress and anxiety and promote cognitive functioning. The main outcomes were related to feasibility (ie, duration and frequency of VR use), safety (ie, adverse events), patient satisfaction, and reasons to withdraw. Physical performance, daily activities, cognitive functioning, anxiety and depression, and the quality of life were measured before and after. RESULTS: In total, 48 patients were included; 1 (2%) patient did not start VR, and 7 (15%) patients withdrew, mostly due to dizziness. Almost 70% (33/47) of participants reported experiencing any adverse event during VR exercising. However, only 25% (9/36) recalled these events at the end of the intervention period. The majority (27/36, 75%) of the patients described VR as having a positive influence on their recovery, and the global satisfaction score was 67%. The average VR use was 30 minutes per session, 3-4 times a week for 3-6 weeks. The overall use of VR applications was almost equally distributed over the 3 sets of VR exercises (physical, relaxing, and cognitive). However, the use frequency of physical exercises seemed to decrease over time, whereas the use of cognitive and relaxation exercises remained stable. Physical performance and quality of life outcomes were significantly improved after 6 weeks. CONCLUSIONS: VR physical exercises at home is feasible and safe with good acceptance in a significant percentage of patient with post-COVID-19 condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT04505761; https://clinicaltrials.gov/ct2/show/NCT04505761.

The Disease-Modifying Role of Taurine and Its Therapeutic Potential in Coronavirus Disease 2019 (COVID-19).

Taurine is an amino sulfonic acid that is implicated in numerous physiological functions, including the regulation of oxidative stress, which plays an important role in coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), together with other pathophysiological processes. The recent finding of decreased serum taurine levels in SARS-CoV-2-infected patients, in tandem with its potential modulatory role in COVID-19 due to its antiviral, antioxidant, anti-inflammatory, and vascular-related effects, provides a rationale for considering taurine as a beneficial supplement in patients suffering from COVID-19. Here, we reviewed the potential disease-modifying effects of taurine and combined these with the current knowledge on COVID-19 to clarify the potential role of taurine in this respiratory disease.

Mild Coronavirus Disease 2019 (COVID-19) Is Marked by Systemic Oxidative Stress: A Pilot Study.

Oxidative stress has been implicated to play a critical role in the pathophysiology of coronavirus disease 2019 (COVID-19) and may therefore be considered as a relevant therapeutic target. Serum free thiols (R-SH, sulfhydryl groups) comprise a robust marker of systemic oxidative stress, since they are readily oxidized by reactive oxygen species (ROS). In this study, serum free thiol concentrations were measured in hospitalized and non-hospitalized patients with COVID-19 and healthy controls and their associations with relevant clinical parameters were examined. Serum free thiol concentrations were measured colorimetrically (Ellman's method) in 29 non-hospitalized COVID-19 subjects and 30 age-, sex-, and body-mass index (BMI)-matched healthy controls and analyzed for associations with clinical and biochemical disease parameters. Additional free thiol measurements were performed on seven serum samples from COVID-19 subjects who required hospitalization to examine their correlation with disease severity. Non-hospitalized subjects with COVID-19 had significantly lower concentrations of serum free thiols compared to healthy controls (p = 0.014), indicating oxidative stress. Serum free thiols were positively associated with albumin (St. ß = 0.710, p < 0.001) and inversely associated with CRP (St. ß = -0.434, p = 0.027), and showed significant discriminative ability to differentiate subjects with COVID-19 from healthy controls (AUC = 0.69, p = 0.011), which was slightly higher than the discriminative performance of CRP concentrations regarding COVID-19 diagnosis (AUC = 0.66, p = 0.042). This study concludes that systemic oxidative stress is increased in patients with COVID-19 compared with healthy controls. This opens an avenue of treatment options since free thiols are amenable to therapeutic modulation.

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids.

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.

N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019.

Significance: Hydrogen sulfide (H2S) is one of the three main gasotransmitters that are endogenously produced in humans and are protective against oxidative stress. Recent findings from studies focusing on coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shifted our attention to a potentially modulatory role of H2S in this viral respiratory disease. Recent Advances: H2S levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant, and anti-inflammatory actions. Furthermore, many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H2S. Critical Issues: Combining H2S physiology and currently available knowledge of COVID-19, H2S is hypothesized to target three main vulnerabilities of SARS-CoV-2: (i) cell entry through interfering with functional host receptors, (ii) viral replication through acting on RNA-dependent RNA polymerase (RdRp), and (iii) the escalation of inflammation to a potentially lethal hyperinflammatory cytokine storm (toll-like receptor 4 [TLR4] pathway and NLR family pyrin domain containing 3 [NLRP3] inflammasome). Future Directions: Dissecting the breakdown of NAC reveals the possibility of increasing endogenous H2S levels, which may provide a convenient rationale for the application of H2S-targeted therapeutics. Further randomized-controlled trials are warranted to investigate its definitive role.

Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein.

The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein-protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, ß3, and ß4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.

COVID-19: immunopathology, pathophysiological mechanisms, and treatment options.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Could Virtual Reality play a role in the rehabilitation after COVID-19 infection?

Post-COVID-19 patients, particularly those who needed high care, are expected to have high needs for physical, psychological and cognitive rehabilitation. Yet, the resources needed to provide rehabilitation treatment are expected to be inadequate because healthcare systems faced a shortage of high-quality treatment of these symptoms already before the COVID-19 crisis emerged in patients with comparable needs. In this viewpoint, we discuss the potential of Virtual Reality (VR) administering fast, tailor-made rehabilitation at a distance, and offering a solution for the impending surge of demand for rehabilitation after COVID-19. VR consists of a head-mounted display (HMD) that can bring the user by computer-generated visuals into an immersive, realistic multi-sensory environment. Several studies on VR show its potential for rehabilitation and suggest VR to be beneficial in post-COVID-19. The immersion of VR may increase therapy adherence and may distract the patient from experienced fatigue and anxiety. Barriers still have to be overcome to easily implement VR in healthcare. We argue that embedding VR in virtual care platforms would assist in overcoming these barriers and would stimulate the spread of VR therapy, both for post-COVID-19 patients in the present and possibly for other patients with similar rehabilitation needs in the future.

Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors.

AIMS: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors. METHODS AND RESULTS: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations. CONCLUSION: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

SARS-CoV-2 and the sympathetic immune response: Dampening inflammation with antihypertensive drugs (Clonidine and Propranolol).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a pandemic with the United States now carrying the highest number of cases and fatalities. Although vaccines and antiviral agents are the main focus of therapy, here we present a plausible hypothesis to leverage our understanding of neuroimmunomodulation to intervene in the pathophysiology of the disease to prevent death.

Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19).

Angiotensin-converting enzyme 2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID-19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter-regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin-angiotensin-aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID-19 severity and progression, including age, sex, ethnicity, medication, and several co-morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2-expressing organs do not equally participate in COVID-19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID-19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS-CoV-2 infection is crucially important as it has major implications for understanding COVID-19 pathophysiology and the development of evidence-based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers, and RAAS inhibitors. Ultimately, prevention is key to combat COVID-19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID-19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID-19 severity. In addition, we discuss the relevant pathological changes resulting from SARS-CoV-2 infection. Finally, we highlight a selection of potential treatment modalities for COVID-19. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Impact of Video-Mediated Communication on Closed Wound Assessments in Postoperative Consultations: Conversation Analytical Study.

BACKGROUND: Research on the use of video-mediated technology for medical consultations is increasing rapidly. Most research in this area is based on questionnaires and focuses on long-term conditions. The few studies that have focused on physical examinations in video consultations indicated that it poses challenges for the participants. The specific activity of wound assessment through video in postsurgery consultations has not yet been studied. Furthermore, a comparative analysis of face-to-face and video settings on the moment-to-moment organization of such an activity is original. OBJECTIVE: The aim of this study was to examine the impact of video technology on the procedure of postsurgery wound assessment and its limits. METHODS: We recorded 22 postoperative video consultations and 17 postoperative face-to-face consultations. The primary purpose of the consultation was to inform the patient about the final pathology results of the resected specimen, and the secondary purpose was to check on the patient's recovery, including an assessment of the closed wound. The recordings were transcribed in detail and analyzed using methods of conversation analysis. RESULTS: The way that an assessment of the wound is established in video consultations differs from the procedure in face-to-face consultations. In the consultation room, wound assessments overwhelmingly (n=15/17) involve wound showings in the context of surgeons reporting their observations formatted with evidentials ("looks neat") and subsequently assessing what these observations imply or what could be concluded from them. In contrast, wound assessments in video consultations do not tend to involve showing the wound (n=3/22) and, given the technological restrictions, do not involve palpation. Rather, the surgeon invites the patient to assess the wound, which opens up a sequence of patient and physician assessments where diagnostic criteria such as redness or swollenness are made explicit. In contrast to observations in regular consultations, these assessments are characterized by epistemic markers of uncertainty ("I think," "sounds...good") and evidentials are absent. Even in cases of a potential wound problem, the surgeon may rely on questioning the patient rather than requesting a showing. CONCLUSIONS: The impact of video technology on postoperative consultations is that a conclusive wound assessment is arrived at in a different way when compared to face-to-face consultations. In video consultations, physicians enquire and patients provide their own observations, which serve as the basis for the assessment. This means that, in video consultations, patients have a fundamentally different role. These talking-based assessments are effective unless, in cases of a potential problem, patient answers seem insufficient and a showing might be beneficial.