This work used event study to examine the impact of three policies  on changes in the daily COVID-19 infection growth rate at the state level in the US (February through August 2020). The results show the importance of early intervention: shutdowns and mask mandates reduced the COVID-19 infection growth rate immediately after being imposed statewide. Over the longer term, mask mandates had a larger effect on flattening the curve than shutdowns. The increase in the daily infection growth rate pushed state governments to shut down, but reopening led to significant increases in new cases 21 days afterward. The results suggest a dynamic social distancing approach: a shutdown for a short period followed by reopening, combined with universal mask wearing. We also found that the COVID-19 growth rate increased in states with higher percentages of essential workers (during reopening) and higher percentages of minorities (during the mask mandate period). Health insurance access for low-income workers (via Medicaid expansion) helped to reduce COVID-19 cases in the reopening model. The implications for public health show the importance of access to health insurance and mask mandates to protect low-income essential workers, but minority groups still face a higher risk of infection during the pandemic. On 11 March, the WHO declared COVID-19 as a pandemic. By the end of August 2020, 6,045,455 people were infected in the US, and 183,472 had died [The rapid spread of COVID-19 required a quick government response. Social distancing practices are the most efficient way to reduce COVID-19 spread and were implemented in China , South KIn the US, state governments play an important role in providing services and social citizenship rights ,10. ThisThis study examined the relation between the daily growth rate in COVID-19 infection (7-day rolling average) and three state-level polices in the US: shutdowns, reopening, and mask mandates. We analyzed the change in the COVID-19 infection growth rate before and after policy implementation and used dynamic event modeling to capture this relation over time. We were also interested in the role of Medicaid expansion on the COVID-19 spread, and the relation between the demographic structure  and COVID-19 infection growth rate in each policy period. This study addressed the following questions: Which policies are more responsive to an increase in COVID-19 infection growth rates, and which have the greatest impact on reducing the COVID-19 infection growth rate? How is the COVID-19 infection growth rate related to Medicaid expansion, essential workers, and minority groups?Social distancing measures play an important role in COVID-19 prevention. A global-level study found that policies reducing contact among individuals, such as business/school closures and no gatherings, prevented 61 million cases across China, South Korea, Italy, Iran, France, and the US by the end of March 2020 . A studyAlthough the shutdowns helped to reduce the COVID-19 infection rate, they also led to a global economic recession . PovertyWith the lifting of shutdown orders, mask wearing became the primary way to slow the COVID-19 spread around the world ,28,29,30The US states’ responses to COVID-19 provide a unique case study on the role subnational governments play in the pandemic. In contrast to other countries, such as Mainland China, Taiwan, and South Korea, where centralized strategies were implemented to control the COVID-19 spread, in the US, state governments were expected to take the lead ,11,36. TThis study explored the relation between the state-level daily COVID-19 infection growth rate and the date when each state imposed each of the three policies. The daily growth rate is used in other COVID-19 studies to measure the relation between policy implementation and COVID-19 infections ,37,38. Tday i are:The 7-day average infections on day iInfection is used to calculate the growth in the 7-day average COVID-19 infections on day i:We used the same approach to calculate the 7-day average growth in tests.Three policies were examined in this study: shutdowns, reopening, and mask mandates. The New York Times  tracks tCNN tracks the state orders requiring mandated mask wearing . By the The fluctuation of COVID-19 daily infections shown in  illustraThis study selected a three-week period before the earliest policy implementation date and a three-week period after the latest policy implementation date for each policy . The thrIn addition to the three state policies of primary interest, we were also interested in the effects of Medicaid expansion (to cover more low-income residents) on the rate of COVID-19 spread. Thirty-four of 50 states had adopted Medicaid expansion during the period of our study . If a stEssential workers and minority groups are some of the most vulnerable populations in the pandemic ,32. For This study used event study to assess the relation between the daily growth rate of COVID-19 infections and the date of policy implementation. We controlled for Medicaid expansion, vulnerable populations , and the daily test growth rate in each model. The regression model is shown below:day iInfection Growth) = f {policy implementation (8 dummies for time before and after policy enactment), daily test growth rate (7 day average), percentage of essential workers, percentage of minorities, Medicaid expansion}.Daily (7-day average) infection growth rate . For states that never imposed the policy, all the policy variables were set to 0. Event study fitted this research because the event model could detect both the time lag of policy implementation and the reverse-causal relation between COVID-19 cases and future policy . Event sWe ran three event study models in STATA 14 to examine the factors related to the COVID-19 daily infection growth rate over the study period  for threAfter states imposed the mask mandate order, the COVID-19 daily infection growth rate declined by 0.04, 0.04, 0.04, and 0.12 standard deviations, respectively, for the periods 6–10 days, 11–15 days, 16–20 days, and 21 or more days after the order . There wThe impact of Medicaid expansion and the demographic structure on the COVID-19 daily infection growth rate varied across the three policies. None of these variables were significantly related to the COVID-19 infection growth rate in the shutdown model . HoweverSocial distancing practices are the main public health response to COVID-19. States imposed shutdown orders at the beginning of the pandemic and then moved to reopen and to impose mask mandates . This stThis study found that reopening orders resulted in an increase in COVID-19 infection growth rates 21 days after the orders were imposed. Other studies on policy implementation show that US states’ reopening orders were not related to dropping case rates, as would be expected for a public health measure, but rather were related to political partisanship at the state level (Republican control) . ReopeniGlobally, research finds a dynamic approach to social distancing practices: a limited time of shutdown followed by reopening. A global-level study of 16 countries showed that a 50-day suppression followed by 30-day relaxation could significantly lower COVID-19 mortality rates . SimilarReopening orders and mask mandates overlap in time. In an alternative model specification (not shown), we combined the reopening model and mask mandates to examine the relation between daily infection growth and policy implementation during the second wave. The results were similar to our original models: the daily infection growth rate increased during reopening and decreased after states imposed mask mandates. We also found that the infection growth rate increased in states with more essential workers and minorities (see p < 0.05) and a higher percentage of low-income essential workers enrolled in Medicaid .Our study confirms that essential workers and minority populations are more vulnerable during the pandemic ,32,45. Wp < 0.05). A California study found that having insurance coverage from Medicaid does not guarantee access to primary care, which is related to broader structural inequalities [The mask mandate model covers a longer study period, from 18 March to 1 September 2020 . The resualities . The CDCualities . The CDCualities . Collaboualities ,47,48. Tualities .This study has several limitations. First, the reopening date was measured as the earliest date of sector reopening. It may not fully capture the reopening scenario. Future studies could explore the relation between the reopening date in different sectors and the spread of COVID-19. Second, this study focused on shutdown orders during the first wave of the pandemic in the US. Some states imposed shutdown orders again, due to the increase in new cases in November and December 2020—the third wave. Future studies could examine the relation between shutdown orders and COVID-19 spread in the third wave. Third, this study used the executive order as the measure of shutdown policy. Policies can lead to changes in behavior, such as a change in people’s mobility, which can be used to measure the level of shutdown  researchThis study shows the importance of early invention in controlling the COVID-19 spread by assessing the impact of state-level shutdown orders and mask mandates on COVID-19 infection growth rates. Rising infection growth rates pushed state governments to impose shutdown orders, and these orders were effective in reducing infections. Reopening was unrelated to infection rates, but resulted in increased daily infection rates after 21 days. Mask mandates led to reduced infection growth rates after implementation. Our dynamic event study suggests a combination of interventions is the most effective policy response. Shutdown followed by reopening, combined with universal mask wearing, helps to lower the COVID-19 infection growth rate. This dynamic policy approach could potentially balance economic disruption and public health. This research also shows the importance of health insurance coverage, achieved through Medicaid expansion, especially for essential workers. However, structural inequality and health disparities in the social determinants of health contribute to a higher risk for minority groups. By conducting event analysis of three common pandemic response policies across the fifty US states, this study contributes to our global understanding of the importance of subnational policy differences. It also points to the need to expand health insurance coverage and address the structural inequalities that lead to higher infection rates in communities with more minority and essential workers.


We developed and characterized flexible carbon-black doped TPU-based sEMG sensing structures. The structures are directly 3D-printed without the need for an additional post-processing step using a low-cost, consumer grade multi-material FDM printer. A comparison between the gold standard Ag/AgCl gel electrodes and the 3D-printed EMG electrodes with a comparable contact area shows that there is no significant difference in the EMG signals’ amplitude. The sensors are capable of distinguishing a variable level of muscle activity of the biceps brachii. Furthermore, as a proof of principle, sEMG data of a 3D-printed 8-electrode band are analyzed using a patten recognition algorithm to recognize hand gestures. This work shows that 3D-printed sEMG electrodes have great potential in practical applications. Electromyography (EMG) is a technique for measuring the electrical activity produced during muscle contraction. EMG provides useful information about the activity of individual muscles and is therefore widely used in the control of hand and arm assistive devices and prosthesis ,4,5,6,7.Surface electromyography (sEMG) electrodes are currently only available in fixed shapes. Some flexible structures are available, such as the TMSi High Density EMG grids ; howeverAlthough other methods, such as conductive fabrics  or screeThe goal of this study is to explore the potential use of additive manufactured EMG electrodes made of flexible carbon doped thermoplastic polyurethane by comparing their performance to conventional electrodes. Furthermore, a multi-electrode setup for use in real-time gesture detection is shown as a proof of principle application for 3D-printed electrodes.EMG can be recorded either invasively or non-invasively; sEMG gives information about the global muscle activity and is preferable to intramuscular EMG (iEMG) because of its non-invasive nature. The bandwidth of an sEMG signal lies between 0 and about 500 Hz ,16,17. THz ,3. Peak In the body, current is facilitated by ion transport. sEMG electrodes convert the ionic current within the tissue into an electronic current. The electrodes can be classified into two main types: dry and wet electrodes . Both weThe most commonly used electrodes are silver/silver chlorides gel-electrodes (AgCl electrodes). These wet electrodes approximate a perfectly non-polarizable electrode, which is characterized by the free flow of charge between the electrode and the body . AgCl elDry electrodes usually have a higher electrode–skin impedance compared to wet electrodes and are more sensitive to movement artifacts . Dry eleSeveral studies have shown that dry electrodes can give results comparable to wet electrodes after only a few minutes ,26. Pylaver time ,25,27.Due to the relatively high electrode–skin contact impedance, biopotential amplifiers need to have a high input impedance. Webster et al. stated an average contact impedance of 1 at 1 MHz . Biopoteat 1 MHz . An inpuWhen 3D-printing electrodes, it is preferable to make dry electrodes, since dry electrodes are more suited for long-term measurements and because of hygienic reasons. Since biopotential amplifiers nowadays have large input impedances, 3D-printed electrodes do not need to be made from highly conductive materials.Both 3D-printing technologies and the number of available materials have grown significantly in recent years, while the cost of both continues to decrease. To 3D-print sensing structures, dielectric and conductive materials need to be combined into single structures. Two main methods to embed a conductive material into a 3D-printed structure are filling and direct printing.The first method adds conductive properties to the material by filling channels or cavities in a printed object with a conductive filler. Filling is usually an extra processing step that takes place after the printing process ,30,31. Tz-direction) as well, the process is repeated, building up the model layer by layer. To enable the deposition of multiple materials, the printer is fitted with multiple extruders and nozzles.Direct conductive 3D-printing has been demonstrated with the use direct-ink writing using silver particle infused inks or elastomers ,34,35,36Models made using FDM printing are usually made from a rigid thermoplastic, such as polylactic acid (PLA), acrylonitrile butadiene styrene (ABS), glycol-modified PET (PETG), polyvinyl alcohol (PVA) or nylon. However, there is a growing variety of flexible materials available. Most of these materials are thermoplastic polyurethanes (TPU); commonly know materials are NinjaFlex and PolyFlex ,39. SoftTo print conductive structures using FDM printing technologies, the raw thermoplastic material is blended with conductive particles such as carbon black. Currently only a few conductive materials are available; see  of 95 A .m) [An increase of the volume fraction of the conductive particles will reduce the resistivity of the material as modeled by percolation theory. The model predicts that the resistivity of the material (tion (m) ,49,50: and AgCl electrodes were placed on a cloth rinsed in a 0.9% NaCl solution. The measurement was performed in three- and four-point configurations using an LCR meter (HP4284A). The measurement frequency ranged from 20 z-direction) are equal for all sensing structures and are indicated in To characterize the performance of 3D-printed electrodes compared to commercial electrodes, and to gain insight into the influence of electrode size on the EMG signal, sensing structures with varying geometry were 3D-printed. These sensing structures were designed using Fusion 360 . The electrode structures were printed using a modified FlashForge Creator Pro FDM printer , fitted with two direct drive extruders suited for printing flexible materials . A personal computer running slicer software  sliced the CAD model and managed the control of the printer. The structures were printed with a layer height of 150 For single electrode applications, a snap button electrode was designed; see Six healthy adult 18+) volunteers participated in the measurements, which were approved by the faculty ethics committee. Before application of the EMG sensing structures, the skin around the biceps brachii is prepared according to SENIAM recommendations + volunte. If hairFor the first measurement, the subjects were asked to perform three short isometric contractions of 1 s per contraction. To help with the isometric contraction, the subjects were asked to try and lift a table fixed to the floor. The voluntary contraction was measured by asking the subjects to perform elbow flexion followed by extension without any load (concentric contraction); this movement was repeated 3 times. The data obtained from this recording were shown to the researcher in real-time and used to validate the setup and electrode placement.The second measurement was the load test. The subjects were asked to place their elbow on an armrest and to hold a handle that was attached to a load; see During both measurements, the subjects remained seated. Both measurements were repeated for different electrode setups . The first set of measurements compared the gold standard AgCl electrodes  and the 3D-printed electrodes. Therefore, the AgCl and printed sensing structures were placed side-by-side on the biceps . The AgCThe data were loaded into Matlab and further processed. First, the drift and movement artifacts were removed from the signal by a 20 n):From the time domain data, the mean  and support vector machine (SVM) algorithms. The two algorithms were chosen since LDA is fast and has low computational effort, and SVM is more powerful and might allow for better recognition between gestures.Inactivity: for 9 s, the subject stands still to obtain the EMG in the neutral position.The following process is repeated for each class:-Determining maximum voluntary contraction (MVC): 9 s recording with 3 s of inactivity and 6 s of full contraction.-3 s of inactivity followed by 6 s of contraction at 30%, 50% and 70% of the previously determined MVC. The subject receives real-time feedback about the target EMG and MVC.Offline generation of the classifier: building the LDA and SVM classifiers. Performing a 10-fold cross validation using the training data to obtain the confusion matrix.Online testing of the classifier: real-time EMG data are analyzed by the classifier to get real-time feedback of the user’s gesture.The functional evaluation of the 3D-printed electrode structure is based on the classification accuracy of the 3D-printed eight-electrode structure in comparison to eight AgCl electrodes. Three healthy adult (18+) volunteers participated in the measurement, which was approved by the faculty’s ethics committee. The subjects were placed in a comfortable position, either sitting or standing, but with the notion that all the movement training should be performed with the arm in the same position. The skin was prepared according to SENIAM recommendations  and the This procedure was repeated twice, once for the printed electrodes and once for the AgCl electrodes.The time-domain data captured using the D16_IED20 and the AgCl electrodes for a given subject, performing three isometric contractions followed by three concentric contractions, are shown in Tests using the smallest electrode structures with an inter-electrode distance of 10 p-value. These results show that most measurements using the largest electrodes with a diameter of 16 p-values.The functional evaluation of the 3D-printed electrode structures in comparison to the AgCl electrodes is based on the classification accuracy. Some spots of the conductive TPU were seen in the dielectric part . These sz-direction [Due to the nature of the FDM printing process, structures are built up from fields of parallel lines that are stacked onto each other. The contact interfaces between these lines and layers cause the conductivity of the printed structure to be anisotropic ,54, manlirection . FurtherThe four-point measurement  shows thr et al. . Due to  as well .The results of the evaluation between the printed and the AgCl electrodes showed that both electrodes are capable of detecting various levels of muscle activity . In FiguIn the electrode size comparison study, the printed electrodes were swapped sequentially after each measurement with a different type varying in diameter and/or inter-electrode distance. Care was taken to place each electrode at the same location as the previous electrode; however, exact repeatable placement was hard to accomplish. Furthermore, there might be a difference between the subjects in subcutaneous fat layers and muscle size, leading to the large individual differences shown in build-up ,26 and abuild-up ,25,27.The intention of the classifiers is to show the possibility of using 3D-printed electrodes structures to perform online control of prosthetic devices and to compare the 3D-printed electrodes against the AgCl electrodes. Through the results, we were able to prove that the classification accuracy of signal recorded using TPU electrodes is of the same level as the accuracy of the conventional AgCl electrodes. The accuracy came close to values of comparable structures reported by Daley et al.  and Li eThe tested structures presented in this work are relatively simple and flat. However, 3D-printing allows for the fast creation of far more complex structures that could be personalized to the user. A more complex, proof of principle 3D-printed five electrode EMG band is shown in This work shows the potential use of additive manufacturing techniques for the creation of flexible personalized sEMG sensing structures. These structures have been successfully printed on a low-cost consumer-grade multi-material FDM printer modified to extrude flexible TPU materials. The material cost of one sensing structure, containing two electrodes, is only €0.20. Comparison between the gold standard AgCl gel electrodes and the printed EMG electrodes with comparable contact areas showed that there is no significant difference in the EMG signal envelope values. This makes 3D-printed electrodes based on conductive TPU highly suitable for practical applications.The results suggest that 3D-printed electrodes with a size comparable to the gold standard electrodes have a performance advantage compared to smaller 3D-printed electrodes. Large inter-individual differences in the recorded electrode amplitudes were observed both within and between subjects. Even the smallest electrodes, with a diameter of 5 mm, were capable of measuring EMG signals in some individuals. However, these electrodes were shown to be unable to resolve small changes in muscle activity. Overall, this work has shown that 3D-printed electrodes, made from a combination of carbon-doped and regular TPU, display a performance that is largely comparable to the gold-standard AgCl electrodes when paired with the high-quality amplifiers used in this research.


Coronavirus is a virus with potential to target the nervous and respiratory systems. The aim of this work is to establish the prevalence of strokes in COVID19 positive patients in Guinea.All patients with stroke confirmed by brain imaging and COVID-positive PCR were included in this study. Retrospective patient data were obtained from medical records. Informed consent was obtained.The RT-PCR confirmed the initial diagnosis and the chest CT scan provided a good diagnostic orientation. Brain imaging identified ischemic brain lesions. We report the case of four patients with stroke and a COVID-19 incidental finding in Guinea.This work shows that the onset of ischemic stroke associated with COVID-19 is generally delayed, but can occur both early and late in the course of the disease. More attention is needed because the early symptoms of viral attack are not just pulmonary. Coronavirus is one of the major viruses that target the human respiratory system, but it also potentially has neuroinvasive capabilities and can spread from the respiratory tract to the central nervous system (CNS) . NeuroloWe searched the database of the French National Health Safety Agency (ANSS) for patients with acute stroke and suspected characteristics of COVID-19. All patients with image-confirmed, COVID-19 positive strokes were included in the study. Patients who had a complicated inpatient acute stroke pathway or who did not achieve negative RT-PCR or RT-PCR were excluded from the study. Retrospective patient data were obtained from medical records. Informed consent from patients and/or parents was obtained in agreement with the National Health Security Agency (ANSS).It was a 71-year-old man admitted to the emergency room of the Ignace Deen National Hospital for left hemi-body weakness, headache, and partial right hemi-body seizure with a fever of 38.6°. His history included high blood pressure, dyslipidemia. There was no known of COVID- 19 exposure. At the anamnesis, the patient had an altered mental state and non-icteric with a blood pressure of 140/80 mm Hg, a tachycardia of 109 beats per minute, an oxygen saturation of 88%. Neurological examination revealed a pyramidal syndrome of the left flasco-spastic hemi-body, rated at 2/5 proportional. The rest of the examination was unremarkable. MRI and cerebral MRI showed multiple cerebral infarctions with right lateral venus sinus thrombosis visible on the MRI . A curatThe case involved a 58-year-old man with no significant medical history, who presented for sudden onset of left hemiparesis, acute mental confusion, physical asthenia with fever and no known contact with a patient declared positive for COVID-19 according to his entourage. On examination there was tachycardia at 135 beats/minute, tachypnea at 28 cycles/minute, oxygen saturation at 85% and fever at 40°C. The patient was put on oxygen. The emergency ECG showed a complete arrhythmia with atrial fibrillation and a disorder of repolarization. Brain CT scan revealed multiple lacunar infarctions . Within The patient was a 62-year-old woman with a history of hepatitis B, hypertension, type II diabetes and dyslipidemia. She was admitted to the emergency room for right hemi-body weakness, dysarthria, and recent hyposmia in a febrile context with the known exposure to a confirmed case with COVID-19, although this was discovered after admission. General examination revealed tachycardia at 103 beats per minute, blood pressure at 170/90vmm Hg, and temperature at 37.5°C. Cerebral MRI showed bi-hemispheric multiple hypersignals suggestive of multiple cerebral infarctions . The D- The patient was a 53-year-old hypertensive male with type II diabetes who was admitted to the emergency department with transient 25- to 30-minute episodes of right hemiparesis and motor aphasia, hyposmia and recent agueusia with severe physical asthenia. The case history revealed a known exposure with one asymptomatic confirmed case of COVID-19. Vital signs were within normal limits with a fever of 38°C. Initial neurological examination was normal. The brain scan performed did not reveal any acute brain injury. Thus the diagnosis of transient ischemic attack was made. RT-PCR confirmed coronavirus infection and the D-Dimer was 723 μg/L. The chest CT scan was normal. The patient was treated with low molecular weight heparin, hydroxychloroquine 300mg; aspirin, statin, and was transferred to the Infectious Disease Control Centre for follow-up for SARS-COV-2. Following 2 negative RT-PCR 48 hours apart, the patient was declared cured and released .Although ischemic stroke has been recognized as a serious complication of COVID-19 . SeventyAll our patients were asymptomatic at COVID-19 before the vascular event occurred. This result is comparable to that reported by Thomas J. Oxley in a series of 5 cases carried out in New York which found 3 asymptomatic cases at COVID-19 before the stroke and 2 symptomatic cases before the stroke . These rNow the question of management of patients suffering from ischemic stroke related to COVID-19 infection in a highly prothrombotic context becomes inherent to our function given the lack of therapeutic evidence and the major risks associated with their use ,12. We cOur observations suggest that further research is needed to identify the neurological implications of COVID-19 disease given the occurrence of central and peripheral neurological manifestations. Plans should be developed to ensure that the management of stroke is not neglected, although the control of COVID-19 infection is our highest priority. We believe that autopsies of the brain will lead to a better understanding of the mechanisms involving the CNS in the pathophysiology of Neurocovid and thus facilitate management. Ultimately, primary prevention of infection and stroke seems to be the best option available to us.The aggression of the coronavirus on the body leads to neurovascular complications.Stroke can also be indicative of COVID-19 infection.The authors declare no competing interests.


In Coronavirus disease 2019 (COVID-19) subjects, recent evidence suggests the presence of unique coagulation abnormalities. In this study, we performed clot waveform analyses to investigate whether specific modulations are observed in COVID-19 subjects. We analyzed the second derivative of the absorbance in routine APTT tests performed using an ACL-TOP system. We observed high frequencies of abnormal patterns in APTT second-derivative curves that could be classified into an early shoulder type, a late shoulder type, or a biphasic type, high maximum first-derivative and second-derivative peak levels, and a low minimum second-derivative peak level in COVID-19 subjects. These modulations were not observed in subjects with disseminated intravascular coagulation. These abnormal patterns are also observed in patients with lupus anticoagulant, hemophilia, or factor IX deficiency. The plasma fibrinogen levels might also be involved in the abnormal APTT waveforms, especially the high maximum first-derivative and second-derivative peak levels. The abnormal patterns in the APTT second-derivative curves appear with highest frequency at around 2 weeks after the onset of COVID-19 and were not associated with the severity of COVID-19. These results suggest the possible presence of a specific abnormal coagulopathy in COVID-19. Moreover, a high frequency of venous and arterial thromboembolism is observed, even in subjects with mild COVID-198. These unique patterns of laboratory data and the high incidence of thromboembolism suggest that coagulation abnormalities might exist in subjects with COVID-19.Coronavirus disease 2019 (COVID-19), caused by the 2019 novel coronavirus (SARS-CoV-2), is spreading and threatening populations worldwide. Acute respiratory distress syndrome and multi-organ dysfunction in COVID-19 causes mortality in patients with severe COVID-19. Along with these complications, the activation of coagulation is one of the severe complications of COVID-19. Disseminated intravascular coagulation (DIC), which is commonly associated with sepsis, can be observed in patients with severe COVID-19. However, the pattern of DIC in COVID-19 patients reportedly differs from that in subjects with sepsis. In COVID-19 subjects, an elevation in D-dimer is prominent, while thrombocytopenia and the prolongations of PT and APTT are milder9. Theoretically, hypo-oxygenation caused by pneumonia can exacerbate endothelial injuries. Actually, the count of circulating endothelial cells was correlated with the severity of COVID-1910. Another possible mechanism is the involvement of inflammation. Severe COVID-19 is associated with an elevation of inflammatory cytokines, which can increase the expression of tissue factor and the suppression of anticoagulant factors11. A hypofibrinolysis and a high thrombin generation were also reportedly involved in the thrombosis in COVID-1912. Recently, lupus anticoagulant has frequently been observed in COVID-19 subjects, and this could also be another possible mechanism of abnormal coagulopathy13. The involvement of the increased release of tissue factors14, neutrophil extracellular traps15, and direct activation of platelets16 have also been demonstrated. However, the exact mechanisms responsible for the coagulopathy observed in COVID-19 remain to be elucidated.At present, several mechanisms have been proposed to explain the mechanism of abnormal coagulopathy observed in COVID-19 subjects. One proposed mechanism is that SARS-CoV2 infects endothelial cells and is then prone to cause endotheliitis, which results in the acceleration of coagulation17. Several studies have proposed that clot formation curves can suggest some specific diseases19. In the present study, therefore, we aimed to investigate the clot waveforms of APTT in COVID-19 subjects to investigate whether abnormal patterns of clot formation are observable using these laboratory tests.In this study, we focused on the clot waveforms of APTT. Clot waveform analyses provide us with information on fibrin abnormalities and the speed and acceleration of clot formationWe found that the second-derivative curves of APTT tests in several COVID-19 subjects showed abnormal patterns: compared with those for normal subjects Fig. A. The eaWe investigated the frequency of abnormal second-derivative curves by analyzing all the APTT tests together, by analyzing the APTT tests performed when the D-dimer or CRP level was at a maximum during the time course, or by analyzing the APTT tests performed when the subjects visited the hospital for the first time. As shown in Table Next, we investigated the factors associated with the abnormal APTT second-derivative curves. First, we investigated the potential associations between abnormal APTT second-derivative waveforms and other related factors. We observed that the APTT second-derivative waveforms and the fibrinogen levels were both higher in the specimens with an early shoulder or biphasic pattern and that the CRP levels were higher in the specimens with a biphasic pattern, compared with those with a normal pattern, while the D-dimer levels and the platelet counts did not differ according to the waveform pattern Fig. D. The leRegarding the association between the maximum first-derivative peak or the maximum or minimum second-derivative peak and other laboratory data, we found rather strong associations between the maximum first-derivative peak or the maximum second-derivative peak and the plasma fibrinogen levels and a moderate association between the minimum second-derivative peak and the APTT level Fig. . AlthougNext, we investigated the time course of the APTT second-derivative curves of COVID-19 subjects. Figure Figure Lastly, we investigated whether the existence of a biphasic pattern for the APTT second-derivative curve was associated with any of the clinical characteristics that were examined in this study. As shown in Table Regarding the association with the thrombotic events, three subjects suffered from deep venous thrombosis in the present study. Although we cannot demonstrate statistically since the number of the subjects with the events was small, abnormal patterns of APTT clot waveform were observed in all of the three subjects. On the contrary, the maximum first-derivative peak tended to be lower, the maximum second-derivative peak was significantly lower, and the minimum second-derivative peak was significantly higher in the subjects with deep venous thrombosis than those without it . COVID-19 subjects were categorized into three groups: those requiring no oxygen therapy (“mild” group), those requiring oxygen treatment without mechanical respiratory ventilation support (“moderate” group), and those requiring mechanical respiratory ventilation support (“severe” group). The characteristics of the COVID-19 subjects were described in Table 19. We investigated the presence of a biphasic pattern in the clot waveform for the second derivative of the absorbance as well as the parameters calculated from the clot waveform, the maximum peak of the first derivative, and the maximum and minimum peaks of the second derivative. Although the time between the sampling and the performance of the assay was not strictly the same, we performed the APTT assays at least in a few hours after the sampling.The APTT tests were performed using the ACL APTT SyntheSis kit and the ACL-TOP 700 hemostasis testing system , which provides three types of curves: a curve showing the changes in absorbance observed during the APTT measurement; a curve presenting the first derivative of the absorbance, corresponding to the coagulation velocity; and a curve showing the second derivative of the absorbance, corresponding to the coagulation accelerationCRP and D-dimer levels were determined by the latex agglutination immunoassay test . Fibrinogen levels were measured by HemosIL fibrinogen C(II) .P values less than 0.05 were regarded as statistically significant in all the analyses.All the data were analyzed statistically using SPSS . The results were expressed as dot plots or the mean ± S.D. The differences in the existence of an abnormal clot waveform were assessed using a Chi square test. Values for more than three groups were compared using the Kruskal–Wallis test followed by the Games Howell test as a post-hoc test. Correlations were examined using the Spearman correlation test. Supplementary Information.


MATR3-associated distal myopathy is a rare distal myopathy predominantly affecting lower legs as well as wrist- and finger extensors. Whilst most distal myopathies are clinically and genetically well characterized, diagnosis often remains challenging. Pattern-based magnetic resonance imaging (MRI) approaches offer valuable additional information. However, a consistent pattern of muscular affection is missing for most distal myopathies. Thus, the aim of the present study was to establish a disease-specific pattern of muscular involvement in MATR3-associated distal myopathy using whole-body MRI.15 patients  with MATR3-associated distal myopathy were subjected to whole-body MRI. The grade of fatty involution for individual muscles was determined using Fischer-Grading. Results were compared to established MRI-patterns of other distal myopathies.There was a predominant affection of the distal lower extremities. Lower legs showed a severe fatty infiltration, prominently affecting gastrocnemius and soleus muscle. In thighs, a preferential involvement of semimembranous and biceps femoris muscle was observed. Severe affection of gluteus minimus muscle as well as axial musculature, mainly affecting the thoracic segments, was seen. A sufficient discrimination to other forms of distal myopathy based solely on MRI-findings of the lower extremities was not possible. However, the inclusion of additional body parts seemed to yield specificity.Muscle MRI of patients with MATR3-associated distal myopathy revealed a distinct pattern of muscular involvement. The usage of whole-body muscle MRI provided valuable additional findings as compared to regular MRI of the lower extremities to improve distinction from other disease entities.The online version of this article (10.1007/s00415-020-09862-9) contains supplementary material, which is available to authorized users. Distal myopathies are a heterogeneous group of rare muscular disorders that vary in disease onset, mode of inheritance and clinical presentation . Recent Imaging of the musculature offers valuable additional information to facilitate the diagnostic process as specific patterns of muscular involvement—with some muscles being selectively affected whilst others are spared—have been observed in different muscle diseases . There aMatrin-3-associated distal myopathy is a rare late-onset distal myopathy predominantly affecting the lower legs as well as finger and wrist extensors . DysphagIn this study, whole body-MRI scans of patients with genetically proven Matrin-3-associated distal myopathy were used with the aim to identify a specific pattern of muscular affection and to monitor the sequence of involvement. Furthermore, the obtained pattern was compared to findings in other distal myopathies to address the diagnostic value of the identified changes.Patients with genetically confirmed Matrin-3-associated distal myopathy (p.S85C/c.254C > G mutation) who underwent whole-body MRI in the course of routine diagnostic work-up were asked for permission to re-evaluate the obtained data for the present study. 15 patients  out of 8 families were included in the current study. The majority of the patients (9 patients) were in mid-stage of the disease , whilst each three were classified to be in disease onset  and end-stage  disease, respectively. While 4 of the patients  were previously described [Whole-body-Imaging was done on a 3.0 T MRI-system  using two flexible 18-channel transmit/receive surface body coils for neck, thorax, arms, abdomen and pelvis. A 36-channel angiography coil was used for the legs. The patient was placed in the supine position. Imaging included a T1-Weighted Dixon Turbo Spin Echo sequence in an axial plain and 8 mm slice thickness. The total amount of time required for the MRI examination was 45 min. No sedation or contrast agent was used.The grade of affection of the individual muscle was determined using the five-point semi-quantitative grading scale established by Fischer et al. . BrieflyDetermination was conducted by an experienced radiologist (DS) who was blinded to the clinical data. A complete summary showing the individual patients’ determined Fischer-grades can be found in Suppl. Table 1.To establish a comprehensive MRI-pattern of muscular affection, patients were first stratified in regard to disease duration . For pattern definition, only advanced disease stages (e.g. mid- and end-stage) were used. For each individual muscle, average as well as median Fischer grade and standard deviation was determined. Using these parameters, the grade of affection was classified into four categories—not/rarely affected , mild/variable affected , moderately affected  and early/severely affected .To test the reliability of the obtained MRI-pattern, all patients with MATR3-myopathy included in this study were compared to the MRI-pattern of muscular affection identified in this study. The derived MATR3 MRI-pattern was dichotomized, only distinguishing between unaffected (not or mild/variable affected) and affected (moderately and early/severely affected) muscles. In patients, all muscles with a Fischer grade > 1 were considered to be affected. For each patient, the mismatch to the defined MATR3-pattern was determined. In this regard, a mismatch was defined as either a muscle that was affected in the individual patient but not in the defined MATR3-pattern or vice versa a muscle that appeared to be not affected in the individual patient but was defined affected in the MATR3-pattern. A mismatch ≤ 20% of all muscles studied in the individual patient was supposed a good congruency to the MATR3-pattern. Hence, the portion of patients fulfilling this criterion was identified.. served as the basis for pattern definition [Patterns of muscular involvement for the individual distal myopathies were defined on the basis of previous findings in distal myopathies. The work of Bugiardini et alfinition . FurtherThe established literature-based pattern was then compared to MATR3-pattern and mismatch was determined. Again, a mismatch ≤ 20% was defined as relevant congruency.Muscular involvement was mainly symmetrical. A predominant affection of the lower extremities with an emphasis on the lower legs was observed. In lower legs, a predominant involution of soleus muscle as well as medial head of gastrocnemius muscle was detected. However, the anterior and lateral compartment  were also involved in most of the cases, though to a lesser extent. A variable degeneration of lateral head of gastrocnemius muscle was seen. However, the deep posterior compartment was mainly unaffected. In thighs, a selective affection of parts of the hamstring muscles (semimembranosus muscle and the long head of the biceps femoris muscle) was observed whereas the anterior and medial compartments were mostly spared. Imaging of the trunk showed early and severe involvement of the gluteus minimus muscle. In contrast, gluteus medius muscle showed a variable grade of affection while gluteus maximus muscle appeared to be not relevantly involved. Evaluation of the paraspinal musculature revealed a scattered degeneration predominantly affecting thoracic parts of the axial musculature . The cervical and lumbar parts of paraspinal musculature appeared only mildly affected. Except for the deltoid muscle, that—especially in the ventral part—showed a moderate involution, no relevant involvement of the musculature of shoulder and arm was seen. Representative examples of whole body imaging findings in MATR3-myopathy are depicted in Fig. At disease onset, there was already a slight (Fischer Grade 1 and 2) involvement in muscles that appeared to be severely affected in advanced disease stages. Especially, gluteus medius muscle as well as the lower limb muscles  showed mild involution in some of the patients  a mismatch less than 20% of all examined muscles was observed. None of the patients in the disease onset group showed a sufficient match with the MATR3-pattern. A sufficient congruency (defined as mismatch < 20%) was observed for 89% of the patients in mid-stage and 100% of the patients in end-stage disease. An even stricter match to the defined MATR3-pattern (mismatch < 10%) was observed in 5 out of 9 patients in mid-stage disease (55%), while only one specimen (33%) in late-stage disease fulfilled this criterion.To determine the diagnostic practicability of the established MATR3-pattern, it was compared to literature-based lower-limb MRI patterns of other distal myopathies Fig. a. A releIn this study, a comprehensive pattern of muscular involvement in MATR3-associated distal myopathy has been established. To our knowledge, this is the largest cohort of patients with MATR3-myopathy studied so far. Furthermore, whole-body MRI as well as a semi-quantitative, scoring-based evaluation system is used for the first time to evaluate muscular affection in MATR3-myopathy.Overall, the observed muscular involution meets very well with the typical clinical aspects seen in MATR3-myopathy . CoBased on the grading system applied, a comprehensive pattern of muscular affection in MATR3-associated myopathy could be established, that showed a feasible match to the individual patients. However, validation of the MATR3-pattern was achieved solely on the basis of the patients that also served for pattern definition. This obvious limitation of the study mainly relates to the low prevalence of the disease and thus lack of additional individuals for thorough validation. In this regard, the only available publication addressing whole-body MRI in MATR3-associated distal myopathy apart from the present study is a case report describing one french patient . The pat2) leading to diffuse fatty infiltration of the musculature [Overall, there was a good congruency of the MATR3-pattern with the individual muscular affection observed in patients. However, some patients (in particular patient 10 and 11) showed a relevant mismatch. Patient 10 had been subjected to high doses of glucocorticoids (non-related to muscular disease) for several years that might have led to additional muscular involution by means of a corticosteroid-induced myopathy. The discrepancies observed in this patient mainly apply to the proximal muscles of the lower extremity, which are predominantly affected in corticosteroid-induced myopathy , 37. In culature , 39. In Noteworthy, MATR3-patients at disease onset  did not match with the MATR3-pattern. Thus, the established pattern may only be useful in patients that show clinical weakness and not be suitable for early identification of oligosymptomatic patients. However, even patients that were imaged in a comparably short interval to symptom onset  displayed a good congruency to the defined pattern (mismatch 2% each). This suggests that the predominantly affected muscles are consistently involved at an early timepoint in disease progression.When comparing the MATR3-pattern to literature-based patterns of other distal myopathies, a good distinction to most of the disease entities was seen. However, a relevant number of studies on disease-specific patterns were only based on a small sample size or did not apply semi-quantitative scoring systems. Furthermore, in most cases an explicit annotation regarding the individual grade of affection of all studied muscles is missing. Thus, the literature-based patterns used in this study might not fully account for the alterations to be expected in some disease entities. In this context, the missing validation of the defined patterns beyond literature evidence appears to be another limitation of the approach used in this study.Interestingly, none of the myopathies with potential distal phenotype showed a relevant congruency to MATR3-myopathy. This might partly be due to the relevant affection of proximal muscle groups reported in all available MRI-studies concerning these disease entities. Reports addressing MRI-finding in patients with exclusive predominant distal affection are missing (see Suppl. Table 2 for details).Despite the satisfying delineation from most distal myopathies using the findings of the lower limb alone, a relevant similarity was found for six distal myopathies. Hence, a sufficient discrimination on the basis of a sole examination of the lower limbs might not be possible.Studies using whole-body MRI are missing for most of the distal myopathies with relevant congruency to MATR3-associated myopathy. On the basis of the available literature, patterns of gluteal and paraspinal affection found in MYOT-associated distal myopathy were divergent to the findings in MATR3-myopathy. This included also a patient with MYOT-associated distal myopathy overseen in the neuromuscular research centre in Halle. Furthermore, the only available study using whole-body MRI in MYOT-myopathy has reported frequent involvement of rhomboidei muscles as well as variable affection of proximal muscles of the upper extremities . These f. Whether the defined categories of muscular involvement, the used parameters and set margins are applicable for other studies using different disease entities remains elusive.Under this aspect, the usage of whole-body imaging offers additional information regarding sufficient delineation of different disease entities. Thus, the findings of the present study further support the recently published recommendations of the MYO-MRI consortium, emphasizing the role of whole-body MRI in diagnosing and monitoring neuromuscular disorders . WhetherThe approach presented in this study appears to be considerably operational. Integrational use of—among others—clinical presentation, family history and muscle biopsy findings along with MRI-examination should further facilitate the accuracy of discrimination between different distal myopathies. For instance, KLHL9- and ADSSL1-associated distal myopathies are reported to have a rather early onset between 10 and 20 years of age, while first symptoms in MYOT-associated distal myopathy are occurring between 50 and 60 years of age , 41, 42.In summary, the distinct pattern of muscular affection established in this study expands the diagnostic opportunities in MATR3-associated distal myopathy in terms of discrimination to other distal myopathies. It emphasizes the benefits of semi-quantitative, scoring-based approaches and explicit delineation of all studied muscles. Furthermore, the data presented highlights the potential of whole-body examination for further delineation of different disease entities. In this respect, the conclusions drawn from this study do not only apply for distal myopathies but for MRI-based studies in neuromuscular disorders in general.All data used for this study is available in deidentified form in the Electronic Supplementary Material section.Supplementary file 1 (XLSX 24 kb)Supplementary file 2 (XLSX 13 kb)Below is the link to the electronic supplementary material.


Understanding the impact of the COVID-19 pandemic on paediatric non-COVID-19-related care, as well as patient and caregiver concerns and stressors, is critical for informing healthcare delivery. It was hypothesised that high care disruptions and psychological stress would be observed among paediatric and adult CHD patients in the early phase of the pandemic.A cross-sectional, international, electronic survey study was completed. Eligible participants included parents of children with acquired or CHD, adults with CHD, or caregivers of adults with CHD.A total of 1220 participants from 25 countries completed the survey from 16 April to 4 May, 2020. Cardiac care disruption was significant with 38% reporting delays in pre-pandemic scheduled cardiac surgeries and 46% experiencing postponed cardiac clinic visits. The majority of respondents (75%) endorsed moderate to high concern about the patient with heart disease becoming ill from COVID-19. Worry about returning for in-person care was significantly greater than worry of harm to patient due to postponed care. Clinically significant psychological stress was high across the sample including children (50%), adults with CHD (42%), and caregivers (42%).The early phase of the COVID-19 pandemic contributed to considerable disruptions in cardiac care for patients with paediatric and adult CHD. COVID-19-related fears are notable with potential to impact willingness to return to in-person care. Psychological stress is also very high necessitating intervention. Further study of the impact of delays in care on clinical outcomes is warranted. Out of concern for vulnerable patients and healthcare workers, in-person healthcare was drastically reduced and elective surgeries and diagnostic procedures postponed during the early phase of the pandemic.3 and >11 million people living with CHD globally.4 While this population at large is likely not at risk for significant COVID-19-related illness;6 they are highly susceptible to the indirect effects of changes and delays in care delivery related to the pandemic. In addition, this population has significant mental health comorbidities at baseline,9 which additional stressors related to the pandemic could exacerbate. Understanding the extent to which the pandemic has impacted care delivery and stress within the paediatric and adult CHD population can better inform our response and design of care during the course of the pandemic and amidst surges in cases.CHDs are the most common birth defects, with >40,000 congenital cardiac operations performed each year in the Unites States of America,We conducted an international online survey aiming to: 1) describe disruptions in cardiac care among paediatric and adult patients with CHD, 2) assess COVID-19-related and general psychological stress, 3) examine disease- and medical care-related correlates of psychological stress, and 4) determine support needs of patients and their caregivers during the pandemic. It was hypothesised that high care disruptions and psychological stress would be observed among paediatric and adult CHD patients in the early phase of the pandemic.10 and 10-item self-reported NIH Toolbox Perceived Stress Scale12 were administered as validated measures of general life stress. No direct patient identifying information was included. The survey bundle, which took <10 minutes to complete, was administered using Qualtrics survey software  with dynamic routing capabilities. Some questions could be skipped allowing participants to the survey without answering questions they did not know or understand. The study was reviewed and approved by the University of Michigan Institutional Review Board with electronic consent obtained from participants.An electronic survey measuring impact of COVID-19 on cardiac care and related concerns was administered. This survey was developed by an expert, multidisciplinary panel with experience in survey design, psychology, and clinical expertise in multiple domains of cardiac and surgical care. Two parents also reviewed the survey and offered feedback. The survey included fixed response and Likert rating scale items across the following domains: demographic/disease information, COVID-19-related cardiac care disruptions, health concerns, information sources, emotional/behavioural stressors, and support needs (see Online Supplement for survey instrument). In addition, the eight-item parent-reported NIH PROMIS Psychological Stress Experiences Scale14 The survey was also sent via e-mail to patients at our centre who had previously undergone congenital heart surgery and participated in a programme for longitudinal follow-up as previously described.15 The survey was open during the early phase of the pandemic for a 3-week period from 16 April to 4 May, 2020.Eligible participants included 1) a parent of a child or young adult (0–25 years) with CHD, cardiomyopathy or heart transplant, 2) an adult with CHD (18+ years), or 3) a partner or spouse of an adult with CHD who provided caregiving support for >1 year. Participants were recruited through a social media campaign with at least 11 paediatric and adult CHD organisations advertising the survey (see Acknowledgements for participating organisations). This methodology for recruiting patients and obtaining information from individuals with congenital and other rare heart disease has been previously utilised and found to provide valid information by our group.12 and parent-reported NIH PROMIS Psychological Stress Experiences Scale,10 with higher scores indicating more stress. A within-respondent comparison between COVID-19-related healthcare concerns was made using paired t-test. Univariate associations of demographic and disease-specific characteristics with COVID-19-related health concerns and psychological stress were examined using two-sample t-test or analysis of variance, as appropriate. All analyses were performed using SAS version 9.4 , with a statistical significance level of 0.05 using two-sided tests.Data are reported as frequency with percentage for categorical variables and mean ± standard deviation (SD) or median with interquartile range for continuous variables. A five-point Likert scale was used for each item on concerns specific to COVID-19 and healthcare, ranging from “not concerned” to “very concerned,” and was linearly transformed to a 0 to 100-point scale with higher scores indicating more concern. General psychological stress was evaluated by T-scores generated from self-reported NIH Toolbox Perceived Stress ScaleParticipant characteristics are reported in Table Table The majority of participants (66%) received information about COVID-19 from a heart disease support, advocacy, or social media group. Many viewed articles (65%) and webinars (54%). A subset (40%) received COVID-19 information directly from their cardiologist/surgeon/heart centre, with few receiving information specific to them or their condition from their care team or centre (21%).Participants endorsed a number of concerns specific to COVID-19 and their cardiac care or health Table . The greDemographic and disease-specific predictors of COVID-19-related health concerns were examined . Similarly, stress was high across adult CHD patients and parents/caregivers, with 42% with a T-score >60. There were no clinically significant differences in general psychological stress by CHD type across patients and caregivers; however, child stress as reported by parents was greatest among transplant recipients (mean 62.5 ± SD 6.3) compared to all other disease group . Similar to regional differences observed in regard to COVID-19-related health concerns, patient and caregiver psychological stress was significantly higher in the Southern region of the United States of America .Overall, general psychological stress was high among the sample Fig . Per parParticipants reported on their support needs during the pandemic Fig . Many , which have demonstrated utility in cardiovascular settings.21Findings necessitate continued focus on the mental health of cardiac patients and their caregivers. A remarkable proportion of patients and families expressed interest in additional mental health and self-care information. Utilising support and advocacy groups to share evidence-based tips and resources is likely to be favourably received by patients and families. Possibly more important than ever, cardiac care should include mental health screening and referral for intervention for those in need of greater support. Whether in person or virtually, cardiac clinicians are encouraged to assess for mood, anxiety, stress, and coping in their patients. This can be quickly accomplished through the incorporation of visual analogue tools, such as the NCCN Distress Thermometer9 Options for telehealth-based mental health services, which are desired by this population,22 are growing rapidly.23 Increasing referral and access to such services for patients with emerging mental health concerns and those disconnected from previous supports because of the pandemic, such as the large proportion of children and adolescents who receive school-based mental health services,24 should be a priority. Lastly, as healthcare systems and hospitals face financial challenges, maintaining at least the current level of mental health support services for cardiac patients will be critical – both for identifying and intervening upon the distress patients and families are reporting, but also to address concerns related to returning to the hospital or clinic settings for care.Referral to mental health colleagues should be provided for those with positive screens. Nearly, a quarter of study respondents indicated that they desired increased access to psychology or therapy services. This is noteworthy as previous research in adult CHD suggests that the majority of patients with mental health needs do not receive appropriate treatment.25 it is of high likelihood that cardiac care disruptions, COVID-19 health-related concerns, and psychological stress reported by our study participants are impacted by social determinants of health. It is critical that future research examines the role of demographic and social factors as it relates to paediatric and young adult cardiac care and psychological wellbeing during the pandemic, so that targeted interventions and support services can be deployed.It is important to acknowledge the limitations of this survey study. To rapidly implement the survey, very minimal identifying/demographic data were collected, thus, limiting our ability to understand how factors such as race/ethnicity, sex, and socio-economic status may have impacted cardiac care disruptions and psychological stress. Our social media-based recruitment method unlikely sufficiently captured the views and experiences of underrepresented patients and families, including those of racial minority and lower socio-economic status. Given the considerable disproportionate rates of COVID-19 infection and mortality among African Americans in the United States of America,Additionally, due to our social media-based recruitment method, we do not know how many received the survey information but chose not to participate. It is likely that respondents were primarily those with personal internet access and those engaged in heart support or advocacy groups, thus, findings may not be generalisable to the diverse group of patients with heart disease and their families. For example, a large percentage of respondents represented the single-ventricle CHD community, which has a large social media presence. Applicability of findings to the broader CHD community should be cautiously considered. Lastly, the pandemic and society’s response to it has been dynamic and ever-evolving. Data captured in the current study were only a snapshot of experiences at the time, and longitudinal follow-up of cardiac care disruptions, health-related concerns, and psychological stress will be necessary.In sum, this study of paediatric and adult CHD patients and caregivers demonstrated a considerable impact of the COVID-19 pandemic on cardiac care with nearly 40% or more of scheduled cardiac surgeries, catheterisations, and clinic visits postpone. Notable concerns about COVID-19 infection in CHD patients, considerable worries about returning to in-person healthcare, and high rates of clinically significant psychological stress were observed across the study participants in the early phase of the pandemic. Patients and caregivers with complex illness and high healthcare needs at baseline expressed greater concerns about COVID-19 infection than complications from delayed cardiac care. Further study of the impact of delays in care on clinical outcomes is needed. Promoting the physical health of patients with acute and chronic illness during the COVID-19 pandemic will require attending to their emotional needs.


Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes coronavirus disease (COVID-19), is creating an unprecedented burden on health care systems across the world due to its high rate of pneumonia-related hospitalizations. This study presents recommendations for the outpatient management of moderate SARS-CoV-2 pneumonia implemented at the Geneva University Hospital, Switzerland, from April 4 to June 30, 2020 and evaluated the impact of these recommendations on patient safety, patient satisfaction, and overall hospital capacity.Recommendations for the outpatient management of moderate pneumonia implemented in the Geneva University Hospital (PneumoCoV-Ambu) between April 4 and June 30, 2020, were evaluated prospectively. The primary endpoint was hospitalization. Secondary endpoints were: severity of COVID-19 disease based on a 7-points ordinal scale assessed at 1 and 2 months following SARS-CoV-2 infection; patient satisfaction using a satisfaction survey and the analysis of number of beds and costs potentially averted.A total of 36 patients with COVID-19-related pneumonia were followed between April 4 and May 5, 2020. Five patients (14%) were hospitalized and none died over a median of 30 days follow-up. The majority of patients  were satisfied with the ambulatory care they received. These novel recommendations for outpatient management resulted in sparing an estimated potential 124 hospital bed-nights and CHF 6’826 per capita averted hospitalization costs over the three months period.Recommendations developed for the outpatient management of COVID-19-related pneumonia were able to spare hospital capacity without increasing adverse patient outcomes. Widely implementing such recommendations is crucial in preserving hospital capacity during this pandemic. The novel Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) and associated coronavirus disease COVID-19) was declared a pandemic by the World Health Organization (WHO) on March 11, 2020 [9 was decAverting hospitalizations is key to preserving health care capacity across countries profoundly affected by COVID-19. Crucial to these efforts is the development and formal evaluation of guidelines on the outpatient management of COVID-19-related pneumonia. Whilst guidelines have been established for the treatment of COVID-19 associated pneumonia in hospitalized patients , there iIn the Canton of Geneva, Switzerland, the health authorities designated the University Hospital of Geneva (HUG), the largest and only public university hospital in the Canton, as the sole dedicated COVID-19 hospital. At the HUG, patients presenting with mild to moderate COVID-19-related pneumonia were not systematically hospitalized but instead were followed as outpatients in order to preserve the health care capacity. Novel recommendations were developed to fit this purpose. This study is an evaluation to determine the impact of these recommendations on patient safety, patient satisfaction and hospital bed-nights averted between April and June 2020.This study was conducted at the HUG, Switzerland, where in March 2020 the Department of Primary Care Medicine which was put in charge of leading the ambulatory COVID-19 response for the Canton of Geneva. This included setting up dedicated COVID-19 testing centers for the Canton and the development of novel guidelines outlining recommendations for outpatient management  and the Two testing centers were set up; “Area E” was designed to test all patients with asymptomatic or mild disease only whilst patients presenting with moderate to severe disease or those with risk factors  were assessed in the Emergency Department (ED) . All patth and May 5th 2020, who had a positive RT-PCR test result for SARS-CoV-2 with either a nasopharyngeal or oropharyngeal swab specimens, were included in this analysis. The data collection period was prospective from May 6 to June 30, 2020. The Cantonal Commission for Ethics and Research (CCER) has approved this study and the use of oral consent in April 2020.Adult patients presenting with mild-to-moderate respiratory symptoms at the dedicated testing centers (Area E and the ED) at the HUG, between April 4This trial was approved by the Cantonal Research Ethics Commission (CCER), Geneva, Switzerland (protocol number CCER 2020–01518). The COVICARE team obtained informed verbal consent by telephone for the use of the data at the time of diagnosis. A form was sent to them by message (SMS and email) for them to validate this consent in writing. Verbal consent was documented in a coded database (REDCap). In addition, since March 2020 and the beginning of the outbreak, all HUG screening and emergency webpages contain statements informing healthcare users that their clinical data may be collected and used in clinical studies on COVID-19. Any patient who refuses to allow their data to be used must inform the health care provider at the time of care provision. The data were collected prospectively and recorded in an Excel database by the same team who did the follow up consultation. The data collected were then anonymized in Excel for the statistical analysis. Excel database is stored on a protected network of the hospital. Access to the database is limited by a password See .www.covicare24.com).Patients presenting to Area E were tested and then advised to self-isolate at home, where they received a follow-up telephone call from the dedicated COVICARE team , 7 Fig . The COVasymptomatic or presymptomatic infection (test positive for SARS-CoV-2 but have no symptoms), mild illness , moderate illness , severe illness , critical illness  [Patients presenting to the Emergency Department were first assessed for the presence of the hospitalization criteria . These iAFU consultations were conducted by a nurse and a senior physician five days a week. Patients were evaluated in a specific room with standardized protective equipment. Surgical mask and smock during the history-taking and gloves, protective glasses and FFP2 mask during the clinical examination. We did not record any cases of contamination of the healthcare team in the professional setting during this period. During the week-end, patients were assessed using the same protocol in the emergency outpatient unit. The AFU consultation included a reassessment of pneumonia severity, based on the evolution of symptoms, significant alterations in their clinical condition, as well as radiological and laboratory findings . The patData on demographic variables , date of symptom onset and comorbidities were collected in both Area E and the Emergency Department before being coded by the COVICARE team into a protected database. During follow-up consultations at AFU, data on additional symptoms were collected on a dedicated computerized form. These included: dyspnea grading based on the New York Health Association classification , anosmiaIn addition, the COVICARE team performed a follow-up with all patients 30 days after diagnosis, collecting data on any additional consultations with their General Practitioner, COVID-19 related visits to Emergency Department or hospitalizations within 30 days .All data are available in a The primary endpoint was COVID-19-related hospitalizations or death 30 to 60 days following diagnosis. Secondary outcomes were:severity of COVID-19 disease 30 to 60 days after SARS-CoV-2 diagnosis, based on a 7-points ordinal severity scale [Patient satisfaction with the ambulatory management strategies measured by a questionnaire administered by phone two to three months post diagnosis. Satisfaction was evaluated with questions on the patient’s preference for remote monitoring, for hospitalization or other. The questionnaire is available in the Number of spared hospital bed-nights and averted care costs compared with a strategy where all COVID-19 related pneumonia cases had been hospitalized.We used data from the HUG Finance Department in order to estimate the average hospitalization cost for patients with pneumonia. The average hospitalization cost per day for pneumonia from the 2018 management accounts varied from CHF 1,057 for the Geriatrics Department to CHF 2,356 for the General Internal Medicine Department (1CHF 〜 1 USD).For this analysis, we averaged the cost of hospitalization to be CHF 1’706.50 per patient per day. For the duration of hospitalization, we extrapolated from past data for the hospitalization for community-acquired pneumonia as the equivalent data for COVID-19 moderate pneumonia hospitalization at the HUG between April and June 2020 are not yet available. The mean hospitalization stay for community acquired pneumonia varied between three to five days, depending on the age and patient comorbidities. The average length of stay is four days, which resulted in an average hospitalization cost of CHF 6 826 per patient.Outpatient costs were calculated using the cohort of patients consulting the dedicated testing center based on the Emergency Department’s billing service. The average costs were between CHF 500–1000 and included nursing triage, medical consultation and additional tests . In addition to outpatient care, we calculated remote follow-up by the COVICARE team; every 48 hours over a 10 day period  and one in-person follow-up consultation in the dedicated COVID-19 ambulatory care unit (CHF 150). This resulted in an average outpatient cost of CHF 1 150 per patient.In this observational study, we prospectively evaluated a sample of 36 patients who presented to Area E or the Emergency Department and met the criteria as outlined previously. We used descriptive statistics, frequency distributions, and chi-square analyses to characterize the sample and we performed a cursory cost estimate reflecting savings based on in-patient versus outpatient care recommendations.During the study period, 64 patients were identified as having suspected SARS-CoV-2 moderate pneumonia in the dedicated testing center and benefited from a follow up consultation with either the AFU and/or COVICARE. Of these, 25 patients tested negative for COVID-19 and had an alternative diagnosis . Of note, the 6 patients with bacterial pneumonia, defined as radiological unilateral condensation, were not hospitalized. The remaining 39 patients tested positive for SARS-CoV-2 and had pneumonia. Of the 39 patients, one did not consent to take part in the study and two were lost to follow-up, resulting in 36 patients being included in the analyses .Demographic and clinical characteristics of the 36 patients are presented in Regarding comorbidities, 24.6% suffered from pulmonary disease (asthma and obstructive sleep apnea), 6% diabetes, 6% hypertension, 3% cancer, 2.8% were immunocompromised, and 2.8% were obese. On the Charlson Comorbidity Index, which predicts 10-year mortality, 27 patients (72%) had zero points, nine (25%) had one point and one (2.8%) had two points. Amongst the five patients who were subsequently hospitalized, two had zero points and three had one point.During follow-up, all patients reported shortness of breath and 25 (70%) presented with NYHA stage II (slight limitation) or III dyspnea (shortness of breath during limited activity). Eight (22.2%) declared anosmia at follow up, twelve (33.3%) complained of headaches and 13  presented with chest pain. Only five (13%) had a fever at follow up. The CURB-65 score was calculated for each patient during consultation. The majority had zero point  and four  had one point. In those four, two were hospitalized. One patient had blood urea above 7 mmol per liter and one had diastolic blood pressure below 60mmHg. None had a CURB-65 above one point. We assessed the ECOG scale performance status of each patient during the follow-up consultations. Seven  had no impairment , 13  had some restriction in physical activity , ten  were capable of all self-care but unable to carry out any work activities , five (13%) were capable of only limited self-care and were confined to bed or chair for more than 50% of waking hours  and one  was completely disabled . None were deceased . Nearly all patients had had a chest X-ray  at initial evaluation, which had revealed bilateral interstitial infiltrates in 23 patients (64%).In this outpatient cohort, only five patients (14%) required secondary hospitalization . These hAmongst the hospitalized patients, two were hospitalized out of precaution and only needed close monitoring, two patients needed oxygen therapy and one needed intermediate care with non-invasive ventilation . The majMost patients presented with grade 1 or 2 disease severity on the SARS-CoV-2 pneumonia scale, 30 to 60 days after diagnosis. The hospitalized patients presented a higher grade of disease severity, respectively two patients with grade 3 (no need for oxygen), two patients with grade 4 (oxygen therapy needed) and one with grade 5 .The majority  were pleased to have remained as outpatient a result of these novel recommendations and dedicated follow-up. Six patients (16%) would have preferred to be admitted to the hospital; two because of the anxiety of spreading the disease to their entourage, and four patients who were subsequently hospitalized would have preferred to be hospitalized immediately.These novel recommendations for the outpatient management of COVID-19-related mild and moderate pneumonia averted a total of 31 hospitalizations over the period of two months. At an average hospitalization cost of CHF 6 826 per patient, guidelines recommending hospitalization of all mild to moderate cases would have resulted in CHF 245 736 total care costs for the 36 patients. Instead, these novel recommendations resulted in CHF 71 030 total care costs (CHF 36 900 outpatient costs and CHF 34 130 in-patient costs) and thus CHF 174 706 savings. At an average of four nights per hospitalization, the new recommendations also saved 124 hospital bed-nights.In this study we present novel recommendations for the outpatient management of mild to moderate COVID-19-related pneumonia in one of the largest public hospitals in Europe.Our study showed that no deaths and no excess hospitalization occurred as a result of implementing these novel recommendations. With our strategy, costly and unnecessary hospitalizations were avoided and hospital capacity was therefore spared. This approach was well accepted by patients, who reported a high level of satisfaction with the care they received.In USA, numerous studies show that home-health care is better cost-wise, and for the patients and health professionals for the management of chronic disease patients who frequently use the Emergency Department , 14. OurOur recommendations allows patients to be seen every two days in AFU and three quarters of patients were seen within 14 days after the onset of symptoms. Other studies show that the critical period for respiratory decompensation is between the eighth and fifteenth day –17. ThisThe first wave of this pandemic highlighted the need for the development of novel and tailored guidelines for the management of both hospitalized and ambulatory patients suffering from COVID-19. Guidelines are crucial to ensure high standards of care for patients, positive patient outcomes and the safeguarding of healthcare capacity. The latter has been highlighted as a particular challenge in the management of the COVID-19 pandemic. The first wave in spring of 2020, highlighted how even the strongest healthcare systems with some of the highest ICU capacity per capita, such as Northern Italy or the USA [Key to tackling a second wave will be the sharing of lessons learned during the first wave across different regions and settings. Only in doing so, can we shorten the learning curve in our fight against this novel virus. Our hope is that in sharing the approach used in the Canton of Geneva this may result in the adoption of these or similar outpatient guidelines for the management of mild to moderate pneumonia and thus help safeguard hospital capacity in those settings. This study reinforces our management strategies and we hope to extend these guidelines further.To our knowledge, recommendations for the outpatient management of mild to moderate COVID-19-related pneumonia have not been reported so far. By using a strict and uniform protocol, the study was able to ensure reproducibility in the standard of care across all patients, while the long and detailed follow-up ensured robust collection of all relevant clinical data. The strengths of this management is that we offered a viable home-health care options to hospitalization. The patients were remotely follow-up by telephone or with in-patient visit at AFU and were reminded at each consultation of the barrier gestures . In addition, each visit was an opportunity to remind them of the alarm symptoms they should be aware of, thus avoiding delays in treatment.This study presents several limitations. Firstly, the sample size is small, limiting the statistical power of the study. Evaluation of the recommendations across a number of regions and centers in the second wave would lead to further data on individual- and population-level outcomes. The cohort of patients were young, but they too had comorbidities. It is difficult to correlate this population with elderly citizen with various comorbidities but we could extend these findings with older people without prior medical condition and have a better immunity to viral respiratory illnesses. Secondly, the guidelines were implemented and evaluated at a time of reduced hospital capacity, where the healthcare system was rolled-back to its essential functions only in order to provide maximum capacity for COVID-19 care. Evaluation of these recommendations during a second wave, when hospital capacity is unlikely to be rolled-back to the same extend as during the first wave, will provide further insight into operational and practical implications of the guidelines. For example, it is likely that avoiding unnecessary hospitalizations will be even more crucial and that even fewer healthcare personnel will be available to staff the relevant units. Finally, evaluation of the effect of the recommendations on healthcare capacity and costs was limited by the sparse data available on COVID-19 specific data on hospitalization costs and number of hospitalization days. Additional data should become available after the second wave, which would allow an update of these results.Recommendations developed for the outpatient management of COVID-19 moderate pneumonia were able to spare hospital capacity without increasing adverse patient outcomes. Implementing such recommendations more widely, will likely be crucial to preserving hospital capacity during a second wave.S1 Dataset(PDF)Click here for additional data file.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.


It plays a significant role in both physiological and abnormal erythropoiesis and regulates iron homeostasis through modulation of hepcidin. It is abnormally secreted in marrow stromal cells of patients with multiple myeloma (MM), which may reflect the tumor microenvironment. We analyzed the associations of serum GDF-15 with clinical characteristics of 73 MM patients (including asymptomatic MM) and the laboratory indices of renal function, anemia, and inflammation. Baseline serum GDF-15 was studied as the predictor of two-year survival. We defined five clinically relevant subgroups of patients . Increased GDF-15 concentrations were associated with more advanced MM stage, anemia, renal impairment (lower glomerular filtration and higher markers of tubular injury), and inflammation. Most of the results were confirmed in the subgroup analysis. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin were associated with GDF-15 independently of other variables. In the studied MM patients, GDF-15 did not significantly predict survival (p = 0.06). Our results suggest that serum GDF-15 reflects myeloma burden and shares a relationship with several markers of prognostic significance, as well as major manifestations.Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor- These characteristics of GDF-15 suggest its increased concentration may be considered as an integrative, general marker for disease severity and mortality β signaliβ [βRII requires caution and reappraisal [The cellular targets and biological functions of GDF-15 are still being explored. The recent discovery of the brainstem-restricted receptor GFRAL  supportsβ , 35, 36.β2-microglobulin), which fall in line with earlier reports , as well as correlations between circulating GDF-15 and indices of tumor burden  or are invalidated remains to be confirmed. The ability of GDF-15 to regulate erythropoiesis through the suppression of hepcidin, the main regulator of iron metabolism, has prompted further investigations, which have implied an alternating role of GDF-15 in the context of underlying stimuli  [Recombinant GDF-15 has been reported to inhibit hematopoiesis, which falls in line with negative correlations between hemoglobin and increasing levels of GDF-15 observed at present, as well as in prior works  . The livabolism) . In prevabolism) . We obseabolism) ).Induction of hepcidin by GDF-15 may potentially limit the availability of iron for hematopoiesis and provide an alternative explanation for the relationship with anemia. It should be noted that the majority of our patients achieved PR/CR and were subjected to treatment, likely decreasing the levels of hepcidin and GDF-15, which falls in line with the observations from earlier studies . MałyszkIn elderly individuals with anemia of unknown etiology, the moderate elevation of GDF-15 was observed, the latter being strongly correlated with kidney function (creatinine), which was surmised to indicate a mutual relationship between anemia and renal insufficiency . ResearcThere are several weaknesses of the study that have to be emphasized. Due to this study being a single-center investigation, we recruited a heterogenous population in favor of study sample size, which prompted post hoc analysis to delineate patient subgroups of clinical interest. Prior studies in homogenous samples  have already demonstrated that GDF-15 is a candidate marker in myeloma, yet the majority of patients that stand to benefit from biomarker assays throughout the management are not treatment-naive.β2 microglobulin), it is also conceivable that the pronounced concentrations of GDF-15 apparent at more advanced stages of disease relate to impaired glomerular filtration. However, the relationship with urinary NGAL in all clinical subgroups, which is reflective of active inflammation in the tubular compartment, may suggest that a generalized insult  is more mechanistically related to the circulating levels of GDF-15, rather than functional nephron loss.We postulate that GDF-15 may parallel the underlying mechanisms of myeloma pathology occurring in the abnormal ME, and as such, it shares a relationship with tumor burden and disease complications, most prominently related to anemia and kidney injury. Due to the correlations between GDF-15 and other markers of myeloma burden, which are also indicators of renal injury (e.g.,


The development of a vaccine able to prevent infection or severe disease course of SARS-CoV-2 is a priority to stem the current COVID-19 pandemic and to be better prepared for future flare-ups. To accelerate T-cell immunogen design, many current approaches are employing epitope prediction strategies. Although such approaches have great merit, it is also important that unbiased approaches to characterizing the T-cell response to SARS-CoV-2 are incorporated into vaccine design, in order to generate a comprehensive picture of the total virus-specific T-cell response and to define correlates of protective immunity against the virus.Ever since the first identification of binding motifs for T-cell antigens presented by HLA class I molecules by Rammensee and colleagues almost 30 years ago, epitope identification has been greatly facilitated by epitope prediction algorithms . Over thAlthough the initial characterization of eluted HLA class I epitopes by the Rammensee lab in 1991 produced predominantly 9-mer epitopes, there was already the notion of longer and shorter sequences that can be bound and effectively presented by HLA class I molecules ,3. EspecOne major limitation of using predicted epitope sequences of 9 amino acids in T-cell vaccine designs is that T-cell responses to only that specific region will be induced by the vaccine. However, the example of HIV infection (which likely has the best-characterized epitope “landscape” described) shows how this can limit the vaccine-induced response: by (1) screening just 5 amino acids up- and downstream of each described optimal (mostly 9-mer) epitope for suitable anchor positions satisfying the currently known allele-specific binding motif and (2) allowing for an epitope length of 9 to 12 amino acids, the number of potential independent epitopes that could bind the given HLA class I molecule and induce T-cell responses to the same region more than doubles . Thus, iThere are to date more than 20,000 HLA class I alleles described that translate into more than 11,000 different HLA class A, B, and C molecules. For many of these alleles, sequence similarities and structural analyses have allowed grouping them into larger, so-called HLA supertypes that share epitope binding similarities . In factAnother critical limitation that is not properly addressed by most epitope prediction tools is the need to identify appropriate antigen-processing sites that could give rise to predicted, presented epitopes. As the composition of the antigen-processing machinery changes upon proinflammatory signals and can differ between different cell types, currently known prediction algorithms will likely not be suited to estimate the processing efficacy of viral antigens in the context of an infected target cell. Thus, without functional validation, there exists the risk that predicted epitopes may represent great theoretical or actual binder to HLA class I molecules, but they are either not processed at all or not processed at sufficient levels to induce a strong immune response and to sensitize infected target cells for CTL-mediated killing. In addition, the allelic diversity of TAP (transporter associated with antigen processing) genes, which encode for proteins that form a bottleneck for the translocation of processed antigen into the lumen of the endoplasmatic reticulum, are only partly integrated into peptide prediction algorithms.Finally, there are evident advantages in identifying antigens not only to protect from SARS-CoV-2 infection but to develop vaccine candidates that could act against past and future coronavirus outbreaks. This would call for focus on particularly conserved regions between isolates and different coronaviruses, something that can be readily implemented in epitope prediction strategies, even if conservation on an epitope level does not need to be complete. Whether such cross-reactive T-cell responses could indeed mediate cross-protection and are associated with effective control of different coronaviruses, remains to be seen. Of note, emerging data start providing some insights into T-cell effector function profiles that may be protective and those that may be associated with a more severe clinical course of SARS-CoV-2 infection . This isWith the urgency to develop effective measures to control the COVID-19 pandemic and to design vaccine strategies useful to confront future outbreaks and epidemics of SARS-CoV-2 and related coronaviruses, accelerated programs for T-cell immunogen design are needed. T-cell epitope prediction algorithms are an effective tool to narrow down the potential immunogen cargo in a future SARS-CoV-2 vaccine from the total viral proteome. However, approaches exclusively based on 9-mer epitope prediction will potentially miss critically important responses, and even those based on 9-mer and 10-mer epitope prediction have similar shortcomings, for the reasons described above. In addition, a relatively unbiased approach to characterizing the T-cell response using overlapping peptides will facilitate understanding of immune correlates of SARS-CoV-2 control versus disease. The benefit of the predicted 9-mer/10-mer approach would be that, when used in combination with panels of overlapping peptides spanning the viral proteome, optimal epitopes will be more rapidly identified and, at the same time, immune correlates of disease protection evaluated in an unbiased fashion. These considerations should not be overlooked, as invaluable time and resources could be directed in directions that may not yield the desired success.