Digital Health Applications to Establish a Remote Diagnosis of Orthopedic Knee Disorders: Scoping Review.

BACKGROUND: Knee pain is highly prevalent worldwide, and this number is expected to rise in the future. The COVID-19 outbreak, in combination with the aging population, rising health care costs, and the need to make health care more accessible worldwide, has led to an increasing demand for digital health care applications to deliver care for patients with musculoskeletal conditions. Digital health and other forms of telemedicine can add value in optimizing health care for patients and health care providers. This might reduce health care costs and make health care more accessible while maintaining a high level of quality. Although expectations are high, there is currently no overview comparing digital health applications with face-to-face contact in clinical trials to establish a primary knee diagnosis in orthopedic surgery. OBJECTIVE: This study aimed to investigate the currently available digital health and telemedicine applications to establish a primary knee diagnosis in orthopedic surgery in the general population in comparison with imaging or face-to-face contact between patients and physicians. METHODS: A scoping review was conducted using the PubMed and Embase databases according to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) statement. The inclusion criteria were studies reporting methods to determine a primary knee diagnosis in orthopedic surgery using digital health or telemedicine. On April 28 and 29, 2021, searches were conducted in PubMed (MEDLINE) and Embase. Data charting was conducted using a predefined form and included details on general study information, study population, type of application, comparator, analyses, and key findings. A risk-of-bias analysis was not deemed relevant considering the scoping review design of the study. RESULTS: After screening 5639 articles, 7 (0.12%) were included. In total, 2 categories to determine a primary diagnosis were identified: screening studies (4/7, 57%) and decision support studies (3/7, 43%). There was great heterogeneity in the included studies in algorithms used, disorders, input parameters, and outcome measurements. No more than 25 knee disorders were included in the studies. The included studies showed a relatively high sensitivity (67%-91%). The accuracy of the different studies was generally lower, with a specificity of 27% to 48% for decision support studies and 73% to 96% for screening studies. CONCLUSIONS: This scoping review shows that there are a limited number of available applications to establish a remote diagnosis of knee disorders in orthopedic surgery. To date, there is limited evidence that digital health applications can assist patients or orthopedic surgeons in establishing the primary diagnosis of knee disorders. Future research should aim to integrate multiple sources of information and a standardized study design with close collaboration among clinicians, data scientists, data managers, lawyers, and service users to create reliable and secure databases.

Enhanced vitamin K expenditure as a major contributor to vitamin K deficiency in COVID-19.

OBJECTIVES: Vitamin K deficiency consistently associates with worse clinical outcome in COVID-19 patients. However, whether this is due to increased expenditure during inflammation or poor vitamin K status prior to infection remained unknown. METHODS: Dp-ucMGP levels of 128 individuals were measured for the post-MONICA study and were compared to SARS-CoV-2 PCR testing results. RESULTS: Dp-ucMGP levels prior to COVID-19 infection were not significantly different comparing PCR-negative, PCR-positive and not hospitalized, and PCR-positive and hospitalized patients. CONCLUSION: In this study, we demonstrate normal vitamin K status prior to infection in SARS-CoV-2 positive patients, supporting the theory of increased utilisation during disease.

Corrigendum: Effects of Vitamin D and K on Interleukin-6 in COVID-19.

[This corrects the article DOI: 10.3389/fnut.2021.761191.].

Effects of Vitamin D and K on Interleukin-6 in COVID-19.

BACKGROUND: Pathology during COVID-19 infection arises partly from an excessive inflammatory response with a key role for interleukin (IL)-6. Both vitamin D and K have been proposed as potential modulators of this process. METHODS: We assessed vitamin D and K status by measuring circulating 25-hydroxyvitamin D (25(OH)D) and desphospho-uncarboxylated Matrix Gla-Protein (dp-ucMGP), respectively in 135 hospitalized COVID-19 patients in relation to inflammatory response, elastic fiber degradation and clinical outcomes. RESULTS: Comparing good and poor disease outcomes of COVID-19 patients, vitamin 25(OH)D levels were not significantly different. IL-6 levels, however, were significantly higher in patients with poor outcome, compared to patients with good outcome (30.3 vs. 153.0 pg/mL; p < 0.0001). Dp-ucMGP levels as biomarker of extrahepatic vitamin K status was associated with IL-6 levels (r = 0.35; p < 0.0001). In contrast, 25(OH)D levels were only borderline statistically significant correlated with IL-6 (r = -0.14; p <0.050). A significant association was also found between IL-6 and elastic fiber degradation. Contrary to vitamin K status, 25(OH)D did not correlate with elastic fiber degradation. CONCLUSIONS: Dp-ucMGP associates with IL-6 as a central component of the destructive inflammatory processes in COVID-19. An intervention trial may provide insight whether vitamin K administration, either or not in combination with vitamin D, improves clinical outcome of COVID-19.

Comment on Sobczyk, M.K.; Gaunt, T.R. The Effect of Circulating Zinc, Selenium, Copper and Vitamin K1 on COVID-19 Outcomes: A Mendelian Randomization Study. Nutrients 2022, 14, 233.

Sobczyk and Gaunt genetically predicted circulating zinc, selenium, copper, and vitamin K1 levels-instead of directly measuring nutrients in blood-and hypothesized that these levels would associate with SARS-CoV-2 infection and COVID-19 severity [...].

Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019.

BACKGROUND: Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. METHODS: A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K-dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography. RESULTS: dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores. CONCLUSIONS: dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019.

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.

Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study.

The hypercoagulable state observed in COVID-19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID-19 patients. This study included 1154 COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80-1.30]) or length of hospital stay (7.0 [4-12] vs. 7.0 [4-12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05-0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID-19 patients.

Vitamin K epoxide reductase complex subunit 1 (VKORC1) gene polymorphism as determinant of differences in Covid-19-related disease severity.

Covid-19, caused by SARS-CoV-2, has major world-wide health-related and socio-economic consequences. There are large disparities in the burden of Covid-19 with an apparent lower risk of poor outcomes in East Asians compared to populations in the West. A recent study suggested that Covid-19 leads to a severe extrahepatic vitamin K insufficiency, which could lead to impaired activation of extrahepatic proteins like endothelial anticoagulant protein S in the presence of normal hepatic procoagulant activity. This would be compatible with the enhanced thrombogenicity in severe Covid-19. The same study showed that vitamin K antagonists (VKA) that inhibit vitamin K recycling, had a greater impact on procoagulant activity than on the activation of extrahepatic vitamin K-dependent proteins during SARS-CoV-2 infections. A genetic polymorphism in the vitamin K epoxide reductase complex 1, VKORC1 -1639A, is particularly prevalent in East Asia and associates with low vitamin K recycling rates. Carriage of the allele may be regarded as bioequivalent to low-dose VKA use. We speculate that VKORC1 -1639A confers protection against thrombotic complications of Covid-19 and that differences in its allele frequency are partially responsible for the differences in Covid-19 severity between East and West.