Legal and Regulatory Framework for AI Solutions in Healthcare in EU, US, China, and Russia: New Scenarios after a Pandemic

Simple SummaryWe offer an overview of the state of regulation of AI in healthcare in the European Union, the United States of America, the China, and the Russian Federation and future strategies to make AI applications safe and useful.The COVID-19 crisis has exposed some of the most pressing challenges affecting healthcare and highlighted the benefits that robust integration of digital and AI technologies in the healthcare setting may bring. Although medical solutions based on AI are growing rapidly, regulatory issues and policy initiatives including ownership and control of data, data sharing, privacy protection, telemedicine, and accountability need to be carefully and continually addressed as AI research requires robust and ethical guidelines, demanding an update of the legal and regulatory framework all over the world. Several recently proposed regulatory frameworks provide a solid foundation but do not address a number of issues that may prevent algorithms from being fully trusted. A global effort is needed for an open, mature conversation about the best possible way to guard against and mitigate possible harms to realize the potential of AI across health systems in a respectful and ethical way. This conversation must include national and international policymakers, physicians, digital health and machine learning leaders from industry and academia. If this is done properly and in a timely fashion, the potential of AI in healthcare will be realized.

Chest imaging in patients with acute respiratory failure because of coronavirus disease 2019.

PURPOSE OF REVIEW: This review aims to explore the different imaging modalities, such as chest radiography (CXR), computed tomography (CT), ultrasound, PET/CT scan, and MRI to describe the main features for the evaluation of the chest in COVID-19 patients with ARDS. RECENT FINDINGS: This article includes a systematic literature search, evidencing the different chest imaging modalities used in patients with ARDS from COVID-19. Literature evidences different possible approaches going from the conventional CXR and CT to the LUS, MRI, and PET/CT. SUMMARY: CT is the technique with higher sensitivity and definition for studying chest in COVID-19 patients. LUS or bedside CXR are critical in patients requiring close and repeated monitoring. Moreover, LUS and CXR reduce the radiation burden and the risk of infection compared with CT. PET/CT and MRI, especially in ARDS patients, are not usually used for diagnostic or follow-up purposes.

Abdominal Computed Tomography Imaging Findings in Hospitalized COVID-19 Patients: A Year-Long Experience and Associations Revealed by Explainable Artificial Intelligence.

The aim of this retrospective study is to assess any association between abdominal CT findings and the radiological stage of COVID-19 pneumonia, pulmonary embolism and patient outcomes. We included 158 adult hospitalized COVID-19 patients between 1 March 2020 and 1 March 2021 who underwent 206 abdominal CTs. Two radiologists reviewed all CT images. Pathological findings were classified as acute or not. A subset of patients with inflammatory pathology in ACE2 organs (bowel, biliary tract, pancreas, urinary system) was identified. The radiological stage of COVID pneumonia, pulmonary embolism, overall days of hospitalization, ICU admission and outcome were registered. Univariate statistical analysis coupled with explainable artificial intelligence (AI) techniques were used to discover associations between variables. The most frequent acute findings were bowel abnormalities (n = 58), abdominal fluid (n = 42), hematomas (n = 28) and acute urologic conditions (n = 8). According to univariate statistical analysis, pneumonia stage > 2 was significantly associated with increased frequency of hematomas, active bleeding and fluid-filled colon. The presence of at least one hepatobiliary finding was associated with all the COVID-19 stages > 0. Free abdominal fluid, acute pathologies in ACE2 organs and fluid-filled colon were associated with ICU admission; free fluid also presented poor patient outcomes. Hematomas and active bleeding with at least a progressive stage of COVID pneumonia. The explainable AI techniques find no strong relationship between variables.

Left Bell's palsy following the first dose of mRNA-1273 SARS-CoV-2 vaccine: A case report.

Even though no definitive link has been established, Bell's palsy has been described as a potential side effect of SARS-CoV-2 mRNA vaccines in a few reports, and the US Food and Drug Administration has recommended strict surveillance of its occurrence in the vaccinated general population. We present the case of a previously healthy 35-year-old female patient who developed Bell's palsy 12 h after receiving the first dose of the mRNA-1273 vaccine. Her general practitioner performed the diagnosis, and corticosteroid treatment was initiated, with slow symptoms improvement. The neurologist's evaluation and a contrast-enhanced brain Magnetic Resonance Imaging revealed a subtle enhancement of the left facial nerve, confirming the diagnosis of Bell's palsy.

Gastrointestinal Bleeding in Patients with SARS-CoV-2 Infection Managed by Interventional Radiology.

BACKGROUND: This study was conducted to evaluate the technical and clinical success of trans-arterial embolization (TAE) as a treatment of gastrointestinal bleeding (GIB) in Coronavirus Disease 2019 (COVID-19) patients and to describe its safety; moreover, we describe the characteristics of these patients. METHODS: Thirty-four COVID-19 hospitalized patients presented with GIB. Risk factors, drugs administered for COVID-19 infection, and clinical and biological parameters were evaluated. Furthermore, intraprocedural data and outcomes of embolization were analyzed. RESULTS: GIB was more frequent in male. Overweight, hypertension, diabetes, previous cardiac disease, and anticoagulation preadmission (48.5%) were frequently found in our population. Previous or actual COVID Acute respiratory distress syndrome (ARDS) and a high level of D-dimer were encountered in most cases. Upper GIB was more frequent than lower GIB. Technical and clinical success rates of embolization were 88.2% and 94.1%, respectively. The complication rate was 5.9%. CONCLUSIONS: Our study highlights the most frequent characteristics of COVID-19 patients with GIB. Embolization is feasible, effective, and safe.

AIforCOVID: Predicting the clinical outcomes in patients with COVID-19 applying AI to chest-X-rays. An Italian multicentre study.

Recent epidemiological data report that worldwide more than 53 million people have been infected by SARS-CoV-2, resulting in 1.3 million deaths. The disease has been spreading very rapidly and few months after the identification of the first infected, shortage of hospital resources quickly became a problem. In this work we investigate whether artificial intelligence working with chest X-ray (CXR) scans and clinical data can be used as a possible tool for the early identification of patients at risk of severe outcome, like intensive care or death. Indeed, further to induce lower radiation dose than computed tomography (CT), CXR is a simpler and faster radiological technique, being also more widespread. In this respect, we present three approaches that use features extracted from CXR images, either handcrafted or automatically learnt by convolutional neuronal networks, which are then integrated with the clinical data. As a further contribution, this work introduces a repository that collects data from 820 patients enrolled in six Italian hospitals in spring 2020 during the first COVID-19 emergency. The dataset includes CXR images, several clinical attributes and clinical outcomes. Exhaustive evaluation shows promising performance both in 10-fold and leave-one-centre-out cross-validation, suggesting that clinical data and images have the potential to provide useful information for the management of patients and hospital resources.

Remarkable vessel enlargement within lung consolidation in COVID-19 compared to AH1N1 pneumonia: A retrospective study in Italy.

PURPOSE: To investigate the early CT findings in COVID-19 pneumonia as compared to influenza A virus H1N1 (AH1N1), with focus on vascular enlargement within consolidation or ground glass opacity (GGO) areas. METHODS: 50 patients with COVID-19 pneumonia were retrospectively compared to 50 patients with AH1N1 pneumonia diagnosed during the 2009 pandemic. Two radiologists reviewed chest CT scans independently and blindly, with discordance resolved by consensus. Dilated or tortuous vessels within hyperdense lesions were recorded. RESULTS: COVID-19 pneumonia presented with bilateral (96%), peripheral areas of GGO (22%), consolidation (4%) or combined GGO-consolidation (74%). The vascular enlargement sign in COVID-19 pneumonia was much more commonly present in COVID-19 (45/50, 90%) versus AH1N1 pneumonia (12/50, 24%) (p < 0.001). Vascular enlargement was more often present in lower lobes with a peripheral distribution. CONCLUSIONS: Vascular enlargement in consolidative/GGO areas may represent a reasonably common early CT marker in COVID-19 patients and is of uncertain etiology. Although speculative, theoretical mechanisms could potentially reflect acute inflammatory changes, pulmonary endothelial activation, or acute stasis. Further studies are necessary to verify specificity and to study if prognostic for clinical outcomes.

Percutaneous Transhepatic Electrohydraulic Lithotripsy for the Treatment of Difficult Bile Stones.

OBJECTIVES: To evaluate the efficacy and safety of percutaneous transhepatic lithotripsy (PTL) using an electro-hydraulic (EH) system for difficult bile stones. METHODS: We retrospectively evaluated two patients with recurrent cholangitis, jaundice and fever for the presence of difficult bile stones, inaccessible by an endoscopic approach, treated with PTL. Both procedures were conducted using the same protocol, with two different accesses. The treatments were performed using a 10 Fr flexible choledoscopy SpyGlass DSTM for visualization and an EH system for lithotripsy. RESULTS: Technical success, clinical success and complications were evaluated. The two procedures were successfully concluded in both patients without any residual stones in the biliary tree. For both patients, a short follow-up period of six months was available, during which they remained asymptomatic. Neither major nor minor complications were registered. CONCLUSION: PTL was determined to be an effective and safe technique. This procedure allows a direct visualization of the stone, reducing fluoroscopy time and permitting a less invasive and less traumatic method for the percutaneous management of difficult bile stones. Advances in knowledge: The direct visualization, the high quality of the digital view, the adequate length of the device and the less traumatic approach of EH systems represent advantages compared with other available technologies.

Generalized chest CT and lab curves throughout the course of COVID-19.

A better understanding of temporal relationships between chest CT and labs may provide a reference for disease severity over the disease course. Generalized curves of lung opacity volume and density over time can be used as standardized references from well before symptoms develop to over a month after recovery, when residual lung opacities remain. 739 patients with COVID-19 underwent CT and RT-PCR in an outbreak setting between January 21st and April 12th, 2020. 29 of 739 patients had serial exams (121 CTs and 279 laboratory measurements) over 50 ± 16 days, with an average of 4.2 sequential CTs each. Sequential volumes of total lung, overall opacity and opacity subtypes (ground glass opacity [GGO] and consolidation) were extracted using deep learning and manual segmentation. Generalized temporal curves of CT and laboratory measurements were correlated. Lung opacities appeared 3.4 ± 2.2 days prior to symptom onset. Opacity peaked 1 day after symptom onset. GGO onset was earlier and resolved later than consolidation. Lactate dehydrogenase, and C-reactive protein peaked earlier than procalcitonin and leukopenia. The temporal relationships of quantitative CT features and clinical labs have distinctive patterns and peaks in relation to symptom onset, which may inform early clinical course in patients with mild COVID-19 pneumonia, or may shed light upon chronic lung effects or mechanisms of medical countermeasures in clinical trials.

Artificial Intelligence in Predicting Clinical Outcome in COVID-19 Patients from Clinical, Biochemical and a Qualitative Chest X-Ray Scoring System

Purpose: To determine the performance of a chest radiograph (CXR) severity scoring system combined with clinical and laboratory data in predicting the outcome of COVID-19 patients. Materials and Methods: We retrospectively enrolled 301 patients who had reverse transcriptase-polymerase chain reaction (RT-PCR) positive results for COVID-19. CXRs, clinical and laboratory data were collected. A CXR severity scoring system based on a qualitative evaluation by two expert thoracic radiologists was defined. Based on the clinical outcome, the patients were divided into two classes: moderate/mild (patients who did not die or were not intubated) and severe (patients who were intubated and/or died). ROC curve analysis was applied to identify the cut-off point maximizing the Youden index in the prediction of the outcome. Clinical and laboratory data were analyzed through Boruta and Random Forest classifiers. Results: The agreement between the two radiologist scores was substantial (kappa = 0.76). A radiological score ≥ 9 predicted a severe class: sensitivity = 0.67, specificity = 0.58, accuracy = 0.61, PPV = 0.40, NPV = 0.81, F1 score = 0.50, AUC = 0.65. Such performance was improved to sensitivity = 0.80, specificity = 0.86, accuracy = 0.84, PPV = 0.73, NPV = 0.90, F1 score = 0.76, AUC= 0.82, combining two clinical variables (oxygen saturation [SpO2]), the ratio of arterial oxygen partial pressure to fractional inspired oxygen [P/F ratio] and three laboratory test results (C-reactive protein, lymphocytes [%], hemoglobin). Conclusion: Our CXR severity score assigned by the two radiologists, who read the CXRs combined with some specific clinical data and laboratory results, has the potential role in predicting the outcome of COVID-19 patients.

Federated semi-supervised learning for COVID region segmentation in chest CT using multi-national data from China, Italy, Japan.

The recent outbreak of Coronavirus Disease 2019 (COVID-19) has led to urgent needs for reliable diagnosis and management of SARS-CoV-2 infection. The current guideline is using RT-PCR for testing. As a complimentary tool with diagnostic imaging, chest Computed Tomography (CT) has been shown to be able to reveal visual patterns characteristic for COVID-19, which has definite value at several stages during the disease course. To facilitate CT analysis, recent efforts have focused on computer-aided characterization and diagnosis with chest CT scan, which has shown promising results. However, domain shift of data across clinical data centers poses a serious challenge when deploying learning-based models. A common way to alleviate this issue is to fine-tune the model locally with the target domains local data and annotations. Unfortunately, the availability and quality of local annotations usually varies due to heterogeneity in equipment and distribution of medical resources across the globe. This impact may be pronounced in the detection of COVID-19, since the relevant patterns vary in size, shape, and texture. In this work, we attempt to find a solution for this challenge via federated and semi-supervised learning. A multi-national database consisting of 1704 scans from three countries is adopted to study the performance gap, when training a model with one dataset and applying it to another. Expert radiologists manually delineated 945 scans for COVID-19 findings. In handling the variability in both the data and annotations, a novel federated semi-supervised learning technique is proposed to fully utilize all available data (with or without annotations). Federated learning avoids the need for sensitive data-sharing, which makes it favorable for institutions and nations with strict regulatory policy on data privacy. Moreover, semi-supervision potentially reduces the annotation burden under a distributed setting. The proposed framework is shown to be effective compared to fully supervised scenarios with conventional data sharing instead of model weight sharing.

Adverse Events in Coronavirus Disease Patients Management: A Pictorial Essay.

Clinical manifestation of coronavirus disease (COVID-19) varies from asymptomatic to severe clinical forms that can result in acute respiratory distress syndrome or in multiple organ dysfunction syndromes. There are no guidelines, based on randomized controlled trials, for the treatment of COVID-19 patients. The treatment is based on antiviral drugs, invasive and non-invasive ventilation supports, and anticoagulant therapy. This is a pictorial essay covering the multiple adverse events encountered during the treatment of COVID-19 patients in an area with a high pandemic incidence. Adverse events are defined as unexpected events following treatment for the infection. The cases described would be useful in aiding early diagnosis, limiting and improving the management of serious complications for patients, and allowing rapid and appropriate treatment.

Deep vein thrombosis in COVID-19 patients in general wards: prevalence and association with clinical and laboratory variables.

BACKGROUND: Preliminary reports suggest a hypercoagulable state in COVID-19. Deep vein thrombosis (DVT) is perceived as a frequent finding in hospitalized COVID-19 patients, but data describing the prevalence of DVT are lacking. OBJECTIVES: We aimed to report the prevalence of DVT in COVID-19 patients in general wards, blinded to symptoms/signs of disease, using lower extremities duplex ultrasound (LEDUS) in random patients. We tested the association of DVT with clinical, laboratory and inflammatory markers and also reported on the secondary endpoint of in-hospital mortality. PATIENTS/METHODS: n  = 263 COVID-19 patients were screened with LEDUS between March 01, 2020 and April 05, 2020 out of the overall n = 1012 admitted with COVID-19. RESULTS: DVT was detected in n = 67 screened patients (25.5%), n = 41 patients (15.6%) died during the index hospitalization. Multiple logistic regression demonstrated that only C-reactive protein (odds ratio 1.009, 95% CI 1.004-1.013, p < 0.001) was independently associated with the presence of DVT at LEDUS. Both age (odds ratio 1.101, 95% CI 1.054-1.150, p < 0.001) and C-reactive protein (odds ratio 1.012, 95% CI 1.006-1.018, p < 0.001) were instead significantly independently associated with in-hospital mortality. CONCLUSIONS: The main study finding is that DVT prevalence in COVID-19 patients admitted to general wards is 25.5%, suggesting it may be reasonable to screen COVID-19 patients for this potentially severe but treatable complication, and that inflammation, measured with serum C-reactive protein, is the main variable associated with the presence of DVT, where all other clinical or laboratory variables, age or D-dimer included, are instead not independently associated with DVT.

Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19.

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleeding.

Chest X-ray findings in a large cohort of 1117 patients with SARS-CoV-2 infection: a multicenter study during COVID-19 outbreak in Italy.

To describe radiographic key patterns on Chest X-ray (CXR) in patients with SARS-CoV-2 infection, assessing the prevalence of radiographic signs of interstitial pneumonia. To evaluate pattern variation between a baseline and a follow-up CXR. 1117 patients tested positive for SARS-CoV-2 infection were retrospectively enrolled from four centers in Lombardy region. All patients underwent a CXR at presentation. Follow-up CXR was performed when clinically indicated. Two radiologists in each center reviewed images and classified them as suggestive or not for interstitial pneumonia, recording the presence of ground-glass opacity (GGO), reticular pattern or consolidation and their distribution. Pearson's χ2 test for categorical variables and McNemar test (χ2 for paired data) were performed. Patients mean age 63.3 years, 767 were males (65.5%). The main result is the large proportion of positive CXR in COVID-19 patients. Baseline CXR was positive in 940 patients (80.3%), with significant differences in age and sex distribution between patients with positive and negative CXR. 382 patients underwent a follow-up CXR. The most frequent pattern on baseline CXR was the GGO (66.1%), on follow-up was consolidation (53.4%). The most common distributions were peripheral and middle-lower lung zone. We described key-patterns and their distribution on CXR in a large cohort of COVID-19 patients: GGO was the most frequent finding on baseline CXR, while we found an increase in the proportion of lung consolidation on follow-up CXR. CXR proved to be a reliable tool in our cohort obtaining positive results in 80.3% of the baseline cases.

CT and clinical assessment in asymptomatic and pre-symptomatic patients with early SARS-CoV-2 in outbreak settings.

OBJECTIVES: The early infection dynamics of patients with SARS-CoV-2 are not well understood. We aimed to investigate and characterize associations between clinical, laboratory, and imaging features of asymptomatic and pre-symptomatic patients with SARS-CoV-2. METHODS: Seventy-four patients with RT-PCR-proven SARS-CoV-2 infection were asymptomatic at presentation. All were retrospectively identified from 825 patients with chest CT scans and positive RT-PCR following exposure or travel risks in outbreak settings in Japan and China. CTs were obtained for every patient within a day of admission and were reviewed for infiltrate subtypes and percent with assistance from a deep learning tool. Correlations of clinical, laboratory, and imaging features were analyzed and comparisons were performed using univariate and multivariate logistic regression. RESULTS: Forty-eight of 74 (65%) initially asymptomatic patients had CT infiltrates that pre-dated symptom onset by 3.8 days. The most common CT infiltrates were ground glass opacities (45/48; 94%) and consolidation (22/48; 46%). Patient body temperature (p < 0.01), CRP (p < 0.01), and KL-6 (p = 0.02) were associated with the presence of CT infiltrates. Infiltrate volume (p = 0.01), percent lung involvement (p = 0.01), and consolidation (p = 0.043) were associated with subsequent development of symptoms. CONCLUSIONS: COVID-19 CT infiltrates pre-dated symptoms in two-thirds of patients. Body temperature elevation and laboratory evaluations may identify asymptomatic patients with SARS-CoV-2 CT infiltrates at presentation, and the characteristics of CT infiltrates could help identify asymptomatic SARS-CoV-2 patients who subsequently develop symptoms. The role of chest CT in COVID-19 may be illuminated by a better understanding of CT infiltrates in patients with early disease or SARS-CoV-2 exposure. KEY POINTS: • Forty-eight of 74 (65%) pre-selected asymptomatic patients with SARS-CoV-2 had abnormal chest CT findings. • CT infiltrates pre-dated symptom onset by 3.8 days (range 1-5). • KL-6, CRP, and elevated body temperature identified patients with CT infiltrates. Higher infiltrate volume, percent lung involvement, and pulmonary consolidation identified patients who developed symptoms.