To ensure adequate intensive care unit (ICU) capacity for SARS-CoV-2 patients, elective neurosurgery and neurosurgical ICU capacity were reduced. Further, the Finnish government enforced strict restrictions to reduce the spread. Our objective was to assess changes in ICU admissions and prognosis of traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) during the Covid-19 pandemic.Retrospective review of all consecutive patients with TBI and aneurysmal SAH admitted to the neurosurgical ICU in Helsinki from January to May of 2019 and the same months of 2020. The pre-pandemic time was defined as weeks 1–11, and the pandemic time was defined as weeks 12–22. The number of admissions and standardized mortality rates (SMRs) were compared to assess the effect of the Covid-19 pandemic on these. Standardized mortality rates were adjusted for case mix.n = 123, SAH n = 101). There were no notable differences in case mix between TBI and SAH patients admitted during the Covid-19 pandemic compared with before the pandemic. No notable difference in TBI or SAH ICU admissions during the pandemic was noted in comparison with early 2020 or 2019. SMRs were no higher during the pandemic than before.Two hundred twenty-four patients were included (TBI In the area of Helsinki, Finland, there were no changes in the number of ICU admissions or in prognosis of patients with TBI or SAH during the Covid-19 pandemic. The Covid-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), prompted unprecedented restriction measures to prevent the spread of the virus. In hospitals, major reorganizations, including reschooling of healthcare professionals and reallocation of medical supplies, took place to be able to tackle the expected sharp rise in SARS-CoV-2 infected patients. Also, neurosurgery was affected, as non-emergent surgeries were postponed, and outpatient clinic visits cancelled . HoweverIn Finland, the first wave of Covid-19 hit the Helsinki area the worst. Thus, we saw the closing of borders, restrictions of free movement, and the closing of schools and restaurants under the enforcement of the Emergency Powers Act. Consequently, the incidence of SARS-CoV-2 infection and, thus its imposed burden on the healthcare system, remained relatively low and our capacity to care for emergency neurosurgical cases remained good.Our aim was to give a detailed description regarding admissions and outcomes of patients with TBI and aneurysmal SAH treated in the neurosurgical ICU in Helsinki during the Covid-19 pandemic. Further, we report changes in emergency and non-emergency neurosurgical operations during this period. We hypothesized a decrease in the occurrence of TBIs due to strict regulations limiting movement and travel in the region but a similar occurrence of aneurysmal SAH compared with the previous year.We reviewed all consecutive cases admitted due to aneurysmal SAH or TBI to the neurosurgical ICU of Helsinki University Hospital between 1 January and 31 May 2020 and between 1 January and 31 May 2019. The 2019 period was used as a reference for 2020. As of 2019, the neurosurgical department in Helsinki covers a population of approximately 2.2 million people, of which 1.8 million (82%) are 18 years or older (the catchment area expanded between 2018 and 2019). We included only adults (18 years or older), as children are treated at a different location . In the region of Helsinki and Uusimaa (referred to as the HUS area), treatment of TBIs and SAHs that require intensive care has for decades been centralized at the neurosurgical department in Helsinki. Essentially, all patients with aneurysmal SAH admitted to the hospital are transferred to our unit  . RegardiAs of 17 March 2020 (week 12), the Emergency Powers Act was enforced in Finland. To prevent the spread of SARS-CoV-2, between 27 March (end of week 13) and 15 April (middle of week 16) 2020, travel in and out of the region of Helsinki and Uusimaa (population 1.7 million) was prohibited . Of importance, hospitals situated outside the Uusimaa border but still belonging to the catchment area of Helsinki University Hospital transferred patients requiring neurointensive or neurosurgical care normally. From 3 April (end of week 14) to 31 May (end of week 22), all restaurants, cafes, and bars were closed. From 18 March (middle of week 12) to 14 May (middle of week 20), schools were closedAt the end of March, the Joint Authority of the Helsinki and Uusimaa Hospital District started to decrease non-urgent treatment with the goal of doubling current ICU capacity to treat SARS-CoV-2 patients.The frequency of TBI and aneurysmal SAH admissions (separately and jointly) are presented in a stepwise fashion, increasing every week, and as the raw number of admissions every 2 weeks. The number of emergency operations is shown on a weekly basis. The number of SARS-CoV-2 treated in the ICUs in HUS was reported twice a week and is shown as the cumulative number of patients receiving intensive care at that time.Week 12 was defined as the cut-off, as extended measures for stopping the spread were implemented following the enforcement of the Emergency Powers Act. Thus, we divided the patients into two intervals—the early interval includes weeks 1–11  and the late interval includes weeks 12–22 .We report the number of admitted TBI and SAH patients tested for SARS-CoV-2 in 2020. The test was carried out with most unconscious patients whose background information could not rule out SARS-CoV-2.t test.We used the 30-day all-cause mortality as the primary patient outcome of interest. We assessed standardized mortality rates (SMR) for each month and interval. The predicted risk of 30-day mortality was calculated using multivariable logistic regression, accounting for age (as a continuous variable), Glasgow Coma Scale  score on admission (or last reliable assessment before intubation and sedation), and admission pupillary light reactivity . The predicted risk-of-death model was based upon patients admitted in 2019 and tested on patients admitted in 2020. The performance of the model is given as the area under the curve (AUC) of the receiver operating characteristic with 95% confidence interval (CI). SMRs are compared using a All neurosurgical non-emergency and emergency surgeries and neurosurgical endovascular procedures performed during the same periods were anonymously extracted by a surgical manager software program  and the Picture Archiving and Communication System software .The study is part of the ongoing quality control project of brain injury patients treated at our neurosurgical intensive care unit. The research committee of Helsinki University Hospital approved our quality control project and waived the need for informed consent (HUS/26/2018 §134).p = 0.038). In total, 24 patients (11 TBI and 13 SAH patients) were tested for SARS-CoV-2, none being positive.The total study population consisted of 224 patients (105 admitted in 2019 and 119 admitted in 2020). Patient characteristics according to admission year are shown in Table In comparison with 2019, no major changes in the number of admissions were seen in 2020 on a biweekly basis .The AUC of the predicted risk of death model was 0.88 , including all TBI and SAH patients admitted in 2020. For TBI patients admitted in 2020, the AUC was 0.85 , and in SAH patients admitted in 2020, the AUC was 0.90 . There was no notable difference in SMRs (Fig. We found that the number of TBI and aneurysmal SAH patients admitted to the neuro-ICU stayed the same during the Covid-19 pandemic compared with the previous year. Furthermore, we did not see any increase in risk of death related to TBI or SAH. The number of emergency and non-emergency neurosurgical operations was lower during the Covid-19 outbreak compared with the same timeframe in 2019.Although the first SARS-CoV-2 infection was reported in Finland in January 2020 when a foreign tourist tested positive, it was not until March 2020 that the number of positive-tested SARS-CoV-2 patients began to rapidly increase. The first domestic SARS-CoV-2 case was on 26 February 2020, having contracted the infection from northern Italy. We began seeing a notable increase in the number of patients requiring intensive care due to SARS-CoV-2 in the beginning of March with a peak reached soon after the Uusimaa province’s lockdown and closing of restaurants in early April.Thus, the first Covid-19 wave hit Finland later than some other countries in Europe, providing extra time to prepare the healthcare system. The operative plan and required procedures to increase ICU capacity were performed efficiently and promptly, which guaranteed sufficient ICU capacity throughout the Covid-19 outbreak, not only to treat SARS-CoV-2 patients but also to treat other patients requiring intensive care. Regarding neurosurgical care in Helsinki, the number of neuro-ICU beds and the number of elective neurosurgery were reduced and specialized neuro-ICU nurses were reallocated to Covid-19-specific ICUs. Still, it was decided that the neuro-ICU was only to treat Covid-19 patients if all other resources have been used. This decision ensured adequate priority and resources to care for emergency neurosurgical patients.Reductions in elective neurosurgery have been reported throughout Europe, resulting in prolonged waiting times for elective surgery , 11. As Interestingly, none of the TBI and aneurysmal SAH patients tested positive during the study period nor were there any known cases of TBI or aneurysmal that would not have been admitted due to SARS-CoV-2. Of note is that the local testing policy was that unconscious patients, in whom a of history SARS-CoV-2 symptoms could not be ruled out, were tested and isolated until negative results.While the focus was to secure sufficient healthcare capacity to treat Covid-19 patients, there were concerns that the diagnosis and treatment of other acute diseases might suffer. Possible reasons for this could include a higher threshold for contacting healthcare services among the general population due to fear of contracting Covid-19 or acute diseases being left unnoticed due to the effects of social distancing . In factIn contrast with our hypothesis, we did not see a decline in ICU admissions due to TBI during the heavy restrictions imposed in Finland. For example, in the European survey study, 18 out of 25 centers reported a lower number of ICU-treated TBI patients. Thus, our finding was surprising, in part because one would assume that self-isolation and closing of bars would prevent head injuries, considering that over a third of TBIs in Finland occur under the influence of alcohol . Yet, thSimilar to our findings, Hecht and coworkers from Berlin reported a decline in all neuro-emergencies at the Charité University Hospital during the Covid-19 pandemic. They specifically reported a no change in the number of aneurysmal SAH and TBI admissions .Although the restrictions did not affect the rate of ICU admissions, we had temporarily fewer emergency operations during the lockdown. Also, the number of emergency craniotomies for TBI declined between the early and late intervals of 2020. However, an overall reduction in emergency operations was also seen in 2019 and may be related to normal seasonal variation instead of Covid-19. As expected, the rate of elective operations declined following the decision to cut non-urgent treatment.The strict nationwide restrictions enforced in Finland due to the Covid-19 pandemic did not result in a notable drop in the number of neuro-ICU-treated TBI or aneurysmal SAH patients. We did not find evidence of worse prognoses in TBI and SAH patients during the Covid-19 pandemic.


Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity in children and adolescents which presents as complex three-dimensional (3D) deformity of the spine and rib cage. This study aimed to estimate the effectiveness and safety of surgical interventions for AIS using Bayesian meta-analysis.The PubMed, EMBASE, and Cochrane Controlled Register of Trials were searched through Oct 1, 2019, without language restrictions. Relevant studies evaluating combined effectiveness and safety of surgical interventions for AIS were included according to eligibility criteria. The primary outcome measures included pulmonary function  and incidence of complications. The secondary outcome measure was change of Cobb angle from pre-operation to post-operation. Data was pooled using a random effects model in pairwise meta-analysis. Bayesian meta-analysis combined direct and indirect evidence using a Bayesian framework.Twenty-eight case-controlled studies with totally 1970 participants were included. This Bayesian meta-analysis combining direct and indirect evidences indicated that posterior fusion with instrumentation without thoracoplasty (PSF) had the highest probability to achieve better pulmonary function and lower complication rate; video assisted anterior fusion with instrumentation without thoracoplasty (VAT) had the highest probability to obtain better Cobb angle correction based on analysis of rank probability.This Bayesian meta-analysis demonstrated that PSF had the highest probability to achieve better post-surgical pulmonary function and lower complication rate, which gives a practical recommendation of PSF as a primary surgical treatment for AIS. The results also support statistics that current surgeries adopted more PSF but less open anterior approach surgery and thoracoplasty. More research work is required to address the effectiveness and safety of VAT for treating AIS more convincingly. Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity in children and adolescents which presents as complex three-dimensional 3D) deformity of the spine and rib cage –3. Its pD deformiSurgical interventions aim to terminate the progression of AIS, achieve maximum permanent correction of the 3D deformity, promote appearance by balancing the trunk, and keep lower incidence rate of short-term and long-term complications . The surSeveral traditional pairwise meta-analyses of surgical interventions for treating AIS have been published previously , 16, 17.The objective of this study is to compare the effectiveness and safety of ASR + PSF, VAT+PSF, PSF, ASF, VAT and WT for treating AIS via Bayesian meta-analyses regarding 4 criteria: Cobb angle, absolute forced vital capacity (FVC), absolute forced expiratory volume in 1 second (FEV1) and incidence of complications.This Bayesian meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , and wasDatabases including Cochrane Controlled Register of Trials, PubMed and EMBASE (Jan 1980 to Oct 2019) were used to identify all studies that evaluated the effectiveness and safety of surgical interventions for treating AIS, with the searching strategy being: (Adolescent idiopathic scoliosis) AND  AND . The titles and abstracts were screened by two independent reviewers to exclude any reports that did not assess the effectiveness and safety of surgical treatment for AIS. Full texts of the remaining articles were reviewed to identify studies that met inclusion criteria.The inclusion criteria were: (1) target population: pediatric patients suffered from AIS; (2) interventions: ASR + PSF, VAT+PSF, PSF, ASF, VAT and WT for treating AIS; (3) methodological criteria: Controlled clinical trials.The exclusion criteria were: (1) target population: patients with other type of scoliosis; (2) interventions: conservative treatments or surgical treatments except those that were above-mentioned; (3) methodological criteria: case series.The primary outcome measures include pulmonary functions (change of absolute FVC and FEV1 from pre-operation to post-operation) and incidence of complications . The secondary outcome measure was change of Cobb angle from pre-operation to post-operation.For each trial, we gathered data on study type, sample size, interventions and follow-up. In addition, the following clinical data were also extracted if available: the Cobb angle from pre-operation and post-operation to calculate the change of Cobb angle, absolute FVC and FEV1 from pre-operation and post-operation to calculate the change of absolute FVC and FEV1, and incidence of complications. Two researchers extracted the data independently according to the pre-specified inclusion and exclusion criteria. Disagreements were resolved by discussion.The Newcastle-Ottawa Scale was used to assess the quality of case-controlled trials in terms of selection and comparability of the study groups, and determination of outcomes, with a maximum of nine points using the criteria listed in Table Sdrugis.org). In each study, the odds ratio (OR) was calculated for dichotomous outcomes, and mean differences (MDs) was calculated for continuous outcomes. Both were presented with 95% confidence interval (CI). The pooled estimates of ORs or standardized MDs and 95% CI of four outcomes  were determined. Heterogeneity in each result was assessed by chi-squared and I2 statistic.Pairwise meta-analysis was performed with a random effects model using ADDIS software  for each result to calculate the variance parameters were performed to determine whether results were reliable.Bayesian meta-analysis combined direct and indirect evidences within a Bayesian framework. The Bayesian framework was performed by ADDIS statistical software (version 1.16.6). Convergence was assessed using the Brooks-Gelman-Rubin method. This method compares within-chain and between-chain variance to calculate the potential scale reduction factor (PSRF) for which a value close to “1” indicates approximate convergence has been reached . InconsiFigure Table As assessed by the Newcastle-Ottawa Scale, one case-controlled study  was awarEleven trials were included in this Bayesian meta-analysis. The network of comparisons on change of absolute FVC is shown in Fig. Twelve trials were included in this Bayesian meta-analysis. The network of comparisons on change of absolute FEV1 is shown in Fig. Fourteen trials were included in this Bayesian meta-analysis. The network of comparisons on incidence of complications was shown in Fig. Twenty trials were included in this Bayesian meta-analysis. The network of comparisons on change of Cobb angle is shown in Fig. In general, the results obtained from the pairwise meta-analysis closely matched those from the Bayesian meta-analysis. Table This Bayesian meta-analysis pooled the data from 28 case-controlled trials, with 1970 participants distributed in ASR + PSF, VAT+PSF, PSF, ASF, VAT or WT groups. To best of our knowledge, this is the first Bayesian meta-analysis combining direct and indirect evidences to provide comprehensive comparisons among multiple surgical interventions for treating AIS that takes 4 criteria into consideration: change of Cobb angle, absolute FVC and absolute FEV1 from pre-operation to post-operation, and incidence of complications. In this analysis, we found that PSF had the highest possibility to obtain a greater change of absolute FVC and FEV1 and a lower incidence of complications compared with other interventions based on rank probability. Moreover, VAT had the highest possibility to obtain greater change of Cobb angle.Based on the quality assessment evaluated by Newcastle-Ottawa Scale, 9 studies were scored 6 with all others scored at least 7, suggesting that the included studies have moderate or high quality. In the node-splitting analysis, the only inconsistency was found between PSF and VAT when comparing change of absolute FVC. We checked the inclusion and statistical processes to find the reason for the inconsistency and noticed that only one study reported this comparison. However, the results of inconsistency factors demonstrated that there was no inconsistency in this Bayesian meta-analysis. In general, the results from this Bayesian meta-analysis were reliable and robust.Spinal deformity can profoundly affect pulmonary function by alternation of lung development, which may cause early mortality through respiratory failure . So earlIncidence of complications is important to evaluate the safety of different surgical interventions. Chen et al.  previousCobb angle measurement is a traditional method to assess the spine deformity of AIS, which is carried out in the coronal plane using a standard postero-anterior radiograph . PreviouRefering to the classification system, Lenke classification system is the most common classification system for AIS, but it can not definitely decide the surgery strategies. Among the RCTs which we included, most of them didn’t discuss the classification of AIS, they just simply defined severe AIS as the Cobb’s angle for main curve≥90°. So, we only focus on the choice of the surgery approaches for AIS in this analysis. The selection of the upper instrumented vertebra (UIV), lower instrumented vertebra (LIV) and the instrumented segment was not taken into our consideration. For the surgery approaches, we suggest that PSF still is the primary choice for AIS because of the minimal influence on pulmonary function and low complication rate. Moreover, the deformity correction rate of PSF is comparable to the other surgery approaches. However, anterior approach combined with posterior approach might be necessary to the patients with severe AIS for maximum correction of deformity. Compared to ASF approach, VAT approach was more more minimally invasive, and has advantages in deformity correction because of less damage to the tissue and less blood loss. However, ASF approach is also a choice for AIS because the VAT approach has a long learning curve for surgeons. The VAT+PSF approach could deal with the severe AIS, which is the tendency for surgery approaches nowadays. And the WT approach should be avoided as as much as possible because of the adverse effects on pulmonary function.This Bayesian meta-analysis has several limitations. Firstly, this study only included case-controlled studies, because randomized controlled trials are challenging to perform in pediatric population , and theIn summary, this Bayesian meta-analysis demonstrated that PSF had the highest probability to achieve better post-surgical pulmonary function and lower complication rate. Moreover, VAT was believed to have the highest probability to obtain better Cobb angle correction. These results support the current statistics, that more surgeries adopted PSF and less surgeries adopted open anterior approach surgery and thoracoplasty. This analysis also gives a practical recommendation of PSF as a primary surgical treatment for AIS. More research work is required to address the effectiveness and safety of VAT for treating AIS more convincingly.Additional file 1: Table S1. The Newcastle-Ottawa Scale for assessing the quality of case-controlled studies in meta-analyses.


We report a case of central retinal artery occlusion (CRAO) in a patient with a previous history of severe COVID-19 disease. This disease has been associated with inflammatory-induced homeostasis changes leading to endothelial dysfunction and a procoagulant state with multi-organ involvement, but the burden of thromboembolic complications in COVID-19 patients is currently unknown. The pathogenesis of retinal artery occlusions is a multifactorial process where inflammation and hypercoagulation state are established risk factors. Even if our experience may represent a coincidental relationship, it is likely that COVID-19 patients could be at risk of developing retinal vascular occlusions. A focused ophthalmological surveillance is advisable to prevent and manage this possible cause of severe vision loss that has an important impact in health care system. The ongoing pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with inflammatory-induced homeostasis changes leading to a severe coagulopathy with multi-organ involvement . The patThe patient was a 59-year-old male, African ethnicity, with a previous longstanding history of hypertension and hyperuricemia under treatment . He was One week after discharge from the hospital, he presented to our emergency service complaining of painless vision loss in the left eye. The patient noticed a decrease in visual function during his neurorehabilitation stay, but he did not realize how severe it was until he covered the right eye the day before. On examination, the best-corrected visual acuity  was 20/20 in the right eye and light perception in the left eye. Right eye ophthalmologic examination was unremarkable, while the left eye showed a nonreactive mydriasis, and dilated fundus ophthalmoscopy revealed the presence of severe arterial narrowing, retinal whitening in the macular region with loss of the physiological macular reflex and peripheral areas of retinal pigment epithelium hyperpigmentation . OpticalThe COVID-19 disease has been described to induce inflammatory-induced homeostasis changes that predispose to thrombotic disease in both venous and arterial circulation . Post-moIt is also well established that a considerable percentage of subjects infected by the coronavirus develop a mild infection or are asymptomatic, and in these cases the clinical and histopathology data available are limited. Hence, the burden of thromboembolic complications in COVID-19 patients is currently unknown, with some authors suggesting that it may represent an underestimated, large-scale issue .We report a case of a patient that developed a central retinal artery occlusion after a severe COVID-19 disease. CRAO are obstructions of retinal blood flow that result in severe vision loss. They are divided in arteritic CRAO, mainly due to giant cells arteritis, and non-arteritic CRAO, where platelet fibrin thrombi or emboli as a result of atherosclerotic disease are responsible for over two-third of all CRAO cases . HoweverRetinal vascular damage could be correlated to the ocular expression of the angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 is internalized by human cells after binding with the ACE2, which acts as a functional receptor for the virus. The expression of ACE2 has been detected in human aqueous humor and in retinal tissue, particularly in pigmented epithelial cells, photoreceptors and Müller cells. ACE2 plays an important role in the vasoprotective axis of the renin–angiotensin system (RAS) as it counterbalances the vasoconstrictive, proliferative, fibrotic and proinflammatory effects of the ACE–Ang II–angiotensin II type 1 receptor (AT1R) axis generating Angiotensin 1–7 (Ang 1–7).via shedding and proteolytic processing (COVID-19 patients show a depletion of ACE2 function directly following the binding with SARS-CoV-2 and indirectly ocessing . This loocessing . Furtherocessing .To our knowledge, there are only two reports  of patieEven though it is not possible to assert with absolute certainty the association between the CRAO and COVID-19 disease, we have to highlight that the correlation is reasonable. Incidentally, the patient was diagnosed with sickle cell disease, and this condition could elicit retinal vascular occlusions, however these occlusions occur predominantly in small caliber peripheral arterioles and its association with CRAO is rare . We mighIn conclusion, because the association between thrombosis and COVID-19 is becoming clearer, there are unresolved questions regarding its possible impact on retinal pathophysiology, especially in a population with multiple risk factors that might develop an asymptomatic SARS-CoV-2 infection, and for which the routine ophthalmic monitoring has been suspended . HoweverThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The COVID-19 pandemic is causing hundreds of thousands of deaths worldwide.To illustrate the importance of this principle, data on age and sex distribution of the first 4993 COVID-19 deaths in Italy, recorded until 23 March 2020,Lombardy is the region rhat experienced the highest death toll by far, reaching 16 112 death by the end of May 2020. Emilia Romagna and Piedmont reached only about 4000 deaths , followed by the other regions all below 2000 deaths. However, once the underlying age- and sex-structure of the population was accounted for, the picture changed. Lombardy remained the region experiencing the greatest excess mortality with SMTRs almost 20 times higher (SMTR = 1968) than the national average (on 23 March); Valle d’Aosta (SMTR = 1323) was the second region for mortality followed by Emilia Romagna (SMTR = 1034) and Trentino-Alto Adige (SMTR = 924).At the beginning of April, Marche experienced almost double the SMTR compared with Piedmont, but by the beginning of May the relative mortality between the two regions reversed. Veneto, among the morthern regions, was comparatively less affected with the SMTR only four times higher than the national average. Also, it emerged more clearly which regions were most successful in ‘flattening the curve’  as opposed to those regions which were still experiencing COVID-19-related mortality, although at a lower rate of increase .Age- and sex-standardization is essential for monitoring the pandemic in space and over time. Our method has the limitations of assuming that the age- and sex-specific mortality rates remain constant over time (which we are addressing in ongoing work), and that COVID-19 related mortality is coded consistently across regions. However, if every country provided the WHO with the simple data required for calculating the SMTRs, the monitoring of trends across regions and over time would convey realistic approximations with minimal requirement for data, once age- and sex-specific COVID-19 mortality data from adequately representative populations were available.None declared.


The aim of current work is to review the CT findings of COVID-19 in a pictorial study to help the radiologists to be familiar to imaging findings of COVID-19.Coronavirus disease 2019 (COVID-19) is a pandemic highly infectious disease which is first reported in December 2019 in Wuhan, China, and then had its outbreak leads to a global public health emergency. Real-time reverse transcription polymerase chain reaction (RT-PCR) of viral nucleic acid is considered as the reference standard for COVID-19 diagnosis; however, recent studies showed the importance of CT chest in the diagnosis of COVID-19 with high sensitivity.The CT hallmarks of COVID-19 were bilateral peripheral ground-glass opacities, consolidation with the advance of the disease more consolidation is there with linear opacities and crazy-paving pattern as well as halo and reverse halo sign.Early identification of COVID-19 cases is vital. The radiologist should be familiar with the possible findings. Further future studies with pathological correlation will help for more understanding of the imaging findings and its value in assessing of prognosis. Coronavirus disease 2019 (COVID-19) is a pandemic highly infectious disease which is first reported in December 2019 in Wuhan, China, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On January 30, 2020, the World Health Organization (WHO) announced this outbreak as a global public health emergency and raised it to the very high risk on February 28, 2020 .Understanding the clinical presentation of COVID-19 is of big importance; the clinical presentations are variable and can include fever as a major presentation; other symptoms include fatigue and cough, while some literature reported diarrhea and nausea to precede fever. Some cases can be asymptomatic, while elderly cases with comorbidities are more vulnerable for respiratory failure. While patients may have normal or low WBCs, RBCs and platelet count with prolonged activated thromboplastin time and increased CRP –8.Real-time reverse transcription polymerase chain reaction (RT-PCR) of viral nucleic acid is considered as the reference standard for COVID-19 diagnosis –11; howeAccording to the official diagnosis and treatment protocol (6th edition) issued by the National Health Commission of China , CT examCOVID-19 can utilize angiotensin-converting enzyme-2 (ACE2) as the cell receptor , so affeWhile peripheral posterior bilateral ground-glass opacities (GGO) with or without consolidation was the major hallmark of COVID-19, other variable CT findings were reported –31.The aim of current work is to review the CT findings of COVID-19 in a pictorial study to help the radiologists to be familiar to imaging findings of COVID-19.GGO is defined as hazy lung areas of slightly increased attenuation without obscuring the bronchial and vascular margins; it can be caused by partial air displacement attributed to partial airspaces filling or interstitial thickening , 33. It In COVID-19, GGO is predominately peripheral and subpleural, either uni or bilateral –17. In eConsolidation is defined as increase in the pulmonary parenchymal attenuation with obscuration of the vascular and airway wall margins due to pathological replacement of alveolar air by fluids, cells, or tissues. It can be multifocal, patchy, or segmental with subpleural location or along bronchovascular bundles , 33.Literature shows consolidation prevalence to be about 2–64% in COVID-19 cases , 19, 20.Reticular pattern refers to thickening of the pulmonary interstitial structures as interlobular septa and intralobular lines , 33; witThe crazy-paving pattern is a linear pattern superimposed on a GGO background giving the appearance of irregular paving stones (crazy); it can be explained by alveolar edema and acute lung interstitial inflammation , 35. It Air bronchogram refers to the pattern of air-filled bronchi (dark) on the background of opacified alveoli (grey/white)  and was It is described as airway changes ; it was reported in 10–20% of COVID-19 patients , 22, 26.Lung fibrosis was reported at CT studies of COVID-19 cases in previous series  in aboutIt is described as small air spaces within the lung; it can be due to pathological dilatation or air spaces or due to resorption of consolidation; some author described it as cavity , and othIt is described as thin (1–3 mm thickness) curvilinear opacity that is parallel to the pleural surface and less than 1 cm deep to it . It was Pulmonary vessel dilatation, peri- and intralesional, was reported in some series ; howeverNodule is described as a small (less than 3 cm) round, oval, or irregular shaped well or poorly defined opacity in the lung . It was Halo sign is described as ground-glass opacity surrounding a pulmonary nodule or mass and represents hemorrhage which was typically described in angioinvasive fungal infection or hypervascular deposits and was attributed to perifocal hemorrhage , 32, 38.Pleural thickening was reported in COVID-19 with higher incidence than effusion  with preIt describes enlarged lymph nodes (> 1 cm short axis)  which maPericardial effusion was earlier reported as being rare (< 5%) finding in COVID-19 cases and can be explained by the severe inflammatory process; some reports described it with a higher incidence in critical COVID-19 cases than milder cases .So, the CT findings in COVID-19 are variable. While mild cases can show bilateral ground-glass opacities and small areas of subsegmental consolidation with the advance of the disease, there can be bilateral multiple subsegmental and lobular consolidation. In advanced cases, CT can reveal heterogeneous widespread bilateral with air bronchogram and bronchial deformation as well as septal thickening and crazy-paving appearance.Isolation of COVID-19 patients is of critical importance to control its spread; thus, early identification of cases is vital. While GGO and consolidation are on top of COVID-19 CT chest findings, the radiologist should be familiar with other possible findings. Further future studies with pathological correlation will help for more understanding of the imaging findings and its value in assessing of prognosis.


A surface plasmon resonance (SPR) sensor based on gate-controlled periodic graphene ribbons array is reported. Different from the conventional methods by monitoring reflectivity variations with respect to incident angle or wavelength, this approach measures the change in SPR curve against the variation of graphene chemical potential  at both fixed incident angle and wavelength without the need of rotating mirror, tunable filter or spectrometer for angular or wavelength interrogation. Theoretical calculations show that the sensitivities are 36,401.1 mV/RIU, 40,676.5 mV/RIU, 40,918.2 mV/RIU, and 41,160 mV/RIU for analyte refractive index (RI) equal to 1.33, 1.34, 1.35 and 1.36; their figure of merit (1/RIU) are 21.84, 24, 23.74 and 23.69, respectively. Significantly, the enhancement in the non-uniform local field due to the subwavelength graphene ribbon resonator can facilitate the detection in redistribution of protein monolayers modeled as dielectric bricks. Optical biosensors monitor variations of the scattering characteristics of incident light including intensity, phase, wavelength, and angle due to interaction between the target analyte and bioreceptor such as nucleic acid sequences, proteins, antibody, enzymes, and etc. Optical fiber with a tapered small core for single-mode operation designed to serve as a high sensitivity RI sensor was reported2. The resonant waveguide gratings were extensively reviewed3, particularly including applications of sensors for detecting the RI change on the waveguide grating surface.The emergence of the respiratory virus COVID-19 outbreak allows us to know the unprecedentedly urgent need of a rapid and accuracy diagnostic test method. Among the known diagnostic techniques, label-free optical biosensors provide high sensitivity and robustness solutions. Most importantly, such a biosensor can be integrated into a compact device and enables the possibility of bedside (or point-of-care) testing9. Additionally, enhanced absorption of surface plasmons on a periodic array of graphene ribbons for TM-polarization  was reported13. Specifically, the obvious optical absorption due to the SPR on graphene ribbons, particularly on its fundamental resonant mode, was demonstrated10.Surface plasmons are collective oscillation of the free electron gas density on the surface of noble metals or graphene. Through the electromagnetic wave coupling between photon and plasmon, the excitation of SPPs (surface plasmon polaritons) is present with its field exponentially decaying (evanescent wave) along the direction perpendicular to the surface14. A nanodevices for detection and real-time monitoring of biomolecular events using SPR and SPR imaging were thoroughly reviewed; the signal modulation schemes including angle, wavelength, amplitude and phase were discussed, as well as their coupling mechanism15. The SPR imaging techniques incorporating wavelength scanning based on solid-state wavelength filter were reviewed from the perspective of detection speed, sensitivity and portability16. RI sensor using long-range surface plasmon mode, which exhibits symmetric field pattern, was shown to have high sensitivity compared with conventional SPR ones due to low loss17. The plasmonic nanograting was employed to tailor the dispersion of plasmonic response; more specifically, the enhancement in quality (Q) factor further improves the figure of merit (FOM) of the biosensor18. The nanoplasmonic biosensor plays an important role in optical sensors because of its high sensitivity to the change in RI. More specifically, the biomolecular recognition elements on the surface of biosensors recognize and capture analyte in a liquid sample, causing an increase in the average RI on the sensor surface; several approaches for detecting the RI change were reported23. An effective design approach for achieving the high FOM of a guided-mode resonance sensor made of a grating-waveguide was numerically studied24. Furthermore, by adding a dielectric thin film having a high real part of permittivity for dramatically improving the sensor sensitivity was reported25. In their study, the guided-wave SPR structure can enhance the evanescent field at the interface between silicon and cover. Additionally, by spin-coating the GeSe nanosheets on the surface of noble metal (Au), a SPR sensor can significantly enhance its sensitively26.Moreover, the sensed medium attached to the position where SPR occurs strongly affects the resonance effect. Such a phenomenon has been widely applied in the design of biosensors for detecting the change in RI of an analyte. To mention a few, the literature focused on SPR sensors, which were designed for detecting chemical and biological species, based on the unlocalized surface plasmons propagating along wave-guiding structures were intensively reviewed27. A transmission type SPR-based sensor made of graphene nanoribbons array in infrared (IR) wavelength range was proposed to detect the wavelength shift of the resonant transmission dip due to the RI change of the analyte medium placed on the sensor surface28. A graphene-based tunable mid-IR biosensor was demonstrated on the protein characterization including both complex RI extraction and vibration fingerprints. The gate-controlled self-biasing graphene ribbons array is dynamically tuned to selectively excite the local SPR mode at different frequencies29.Regarding the biosensors made of graphene ribbons, the researchers detected multiple SPR absorption bands on graphene ribbons by changing the graphene chemical potentialThis research reports the computational design of a biosensor for RI sensing at mid-IR wavelengths. Specifically, the SPR modes supported by graphene nanoribbons are excited by evanescent wave rather than plane wave. The excitation of SPR modes in the nanoresonators (nanoribbons) enables the local-field enhancement around the slit (the region between two adjacent ribbons) edges. The placement of analyte on the surface of nanoresonators strongly affects the resonant condition of surface plasmons, particularly on the fundamental mode. As is well known, the wavelength- and angle-interrogation are the two major approaches for detecting the RI change due to a shift in SPR-curve. Significantly, in this research, graphene chemical potential scan is employed to replace the sophisticated wavelength modulation or incident angle scan. By electronically tuning the gate voltage (dc) to change the chemical potential (Fermi energy) in graphene, one can detect the smallest resolvable RI change of an analyte through the shift in SPR curve (against the variation of gate voltage). Furthermore, the tunable gate voltage can be provided by a high-resolution digital-to-analog converter (DAC) equipped with an amplifier. Furthermore, a periodic dielectric bricks array was employed to model discrete sensing mediums such as protein monolayers. The perturbation on SPR curve due to their redistribution and variation of surface percentage coverage (concentration) were also examined. Such a mechanism can be a potential candidate for designing a cost effective biosensor with acceptable performance parameters.x-axis; they are deposited on a silica , carrier relaxation time  image detection. The detail process of graphene transfer in fabricating the crystalline silicon-graphene-gate oxide structure can be found in Fig. 9 of33. Additionally, the graphene layer between Si and 34. As was reported by the authors, this device is compatible with the conventional integrated circuits process. Regarding the issue of interaction between graphene and 35, the electronic measurement showed that the single layer graphene on 29.The single layer graphene inserted between the crystalline silicon and gate oxide has been successfully implemented in the structure of a graphene photodiode-oxide-semiconductor field effect transistor (PDOSFET) shown in Fig. 8 ofy-axis) is normally incident upon the wedge surface shown in Fig. y-axis is much greater than the operating wavelength; the electric- and magnetic-fields have no variation along that direction. Therefore, a simplified 2D electromagnetic model depicted in Fig. 36 exponentially decaying along the z-axis excites the SPR modes on the graphene ribbons. Notably, because that the period of graphene ribbons array ; therefore, it is more feasible and efficient than the commonly used methods.Figure  entclass1pt{minimaentclass1pt{minimaentclass1pt{minimaWe redraw the reflectance against chemical potential shown in Fig. entclass1pt{minimaentclass1pt{minimaV is the voltage induced on the graphene sheet.To understand the physical insight of wave process involved in the structure, the absorption against wavelength for the same biosensor employed in the previous example is calculated subject to an arbitrary analyte RI such as x-component current density  structure has a significant sensitivity enhancement. Nevertheless, due to the non-uniform evanescent field, the developed sensor can detect the redistribution of discrete analyte as shown in the later section.Furthermore, the three wavelength-selective (resonant) absorption (in blue color) occurring at 40 by fitting a sum of exponential functions to the sampled data of Returning to Fig. To evaluate the performance of this sensor, we calculate the RI sensitivity and figure of merit. The analyte under test is modeled as a uniform dielectric layer with refractive index mentclass2pt{minimThe typical RI detection resolution is around N is the bit number of a DAC and V for Returning to Table  29  to mimic their redistribution. Figure In Fig. 41. Parameter C, in fact, can also be regarded as the protein concentration. Here, C) from 0.1 to 0.05% with a step In the second example, in each unit cell the protein monolayer is positioned at the center of slit, shown in the inset of Fig. y-axis in practical manufacture; that is, the electric- and magnetic-fields are supposed to have no variation along that direction. Due to the periodicity along the x-axis (periodic graphene ribbons array), the electromagnetic fields in each uniform dielectric layer and semi-infinite medium are represented by Rayleigh expansions (or Floquet–Fourier series)45. Owing to the zero thickness approximation of the graphene grating, discontinuity in the tangential component of magnetic fields at the interface (surface of periodic graphene ribbons array) between two uniform mediums equals to the conduction current induced on the graphene strips array. The relationship between tangential electric and magnetic fields can be established via the graphene optical conductivity. Through the conventional mode-matching method, the scattering characteristics of the graphene ribbons array can be determined; however, the Gibbs phenomenon in Floquet–Fourier series due to the discontinuity of tangential electric field causes poor numerical convergence in scattering analysis. Specifically, as was reported47, traditional approach of rigorous coupled-wave analysis experienced a poor convergence in particular under the resonance of surface plasmon-polariton wave. Therefore, local basis functions inherently satisfying the field nature in graphene ribbon and slit regions were employed to modify the input–output relation of the periodic graphene ribbons array while the whole formulation can still fit into the standard procedure of Fourier modal method12. Some of the mathematical formulations together with the numerical convergence check -selective property of the SPR curve is essential. A clear dip allows us to easily identify the RI change. In Fig. 50; however, it is apparent to see that the resonant wavelength is varying in accordance with the change in the slit width. Additionally, the line width of SPR curve is getting wide when the slit width is decreasing. This may be explained as the occurrence of strong mutual coupling between two adjacent ribbons for the case of narrow slit width. Moreover, the coupling is caused by the leakage in resonator10, reducing the quality factor (increase in line width) of SPR curve. Contrarily, the SPR curves gradually converges for In Fig. In Fig. The computational design of an evanescent wave biosensor incorporating the SPR on periodic graphene ribbons array is carried out through the electromagnetic modeling and full-wave simulation. Different from the conventional approach by measuring the shift in SPR with respect to the operating wavelength or incident angle of a TM-polarized light, the self-biasing scheme by tuning the chemical potential of graphene (via modifying applied gate voltage) is implemented to track the SPR response. Moreover, due to ultrastrong Supplementary material 1


Reductions in tumor movement allow for more precise and accurate radiotherapy with decreased dose delivery to adjacent normal tissue that is crucial in stereotactic body radiotherapy (SBRT). Deep inspiration breath-hold (DIBH) is an established approach to mitigate respiratory motion during radiotherapy. We assessed the feasibility of combining modern optical surface-guided radiotherapy (SGRT) and image-guided radiotherapy (IGRT) to ensure and monitor reproducibility of DIBH and to ensure accurate tumor localization for SBRT as an imaging-guided precision medicine.t-test. Finally, the planning target volumes were compared to those of free-breathing plans, prepared as a precautionary measure in case of technical or patient-related problems with DIBH.We defined a new workflow for delivering SBRT in DIBH for lung and liver tumors incorporating SGRT and IGRT with cone beam computed tomography (CBCT) twice per treatment fraction. Daily position corrections were analyzed and for every patient two points retrospectively characterized: an anatomically stable landmark  and a respiratory-dependent landmark . The spatial distance of these points was compared for each CBCT and used as surrogate for intra- and interfractional variability. Differences between the lung and liver targets were assessed using the Welch p < 0.001, paired t-test). After SGRT-based patient set-up, subsequent IGRT in DIBH yielded significantly higher mean corrections for liver targets compared to lung targets . Analysis of spatial distance between the fixed and moveable landmarks confirmed higher interfractional variability (interquartile range (IQR) 6.8 mm) than intrafractional variability (IQR 2.8 mm). In contrast, lung target variability was low, indicating a better correlation of patients’ surface to lung targets .Ten patients were treated with SBRT according this workflow . Planning target volumes could be reduced significantly from an average of 148 ml in free breathing to 110 ml utilizing DIBH (SBRT in DIBH utilizing SGRT and IGRT is feasible and results in significantly lower irradiated volumes. Nevertheless, IGRT is of paramount importance given that interfractional variability was high, particularly for liver tumors. Focused delivery of high radiation doses to an extracranial tumor in few fractions is defined as stereotactic body radiotherapy (SBRT). It has become a commonly available and recognized treatment option for early stage primary tumors of or oligometastases from liver and lung primaries with a high rate of local control, often comparable to surgical resection –3. Due tIn order to compensate for target motion, the International Commission on Radiation Units and Measurements (ICRU) introduced the concept of an internal margin to account for respiratory-induced changes in size, shape and position of a clinical target volume (CTV) . The addTM , or active breathing control devices, such as ABCTM , which both reduce residual spatial uncertainties to 1–2 mm in standard radiotherapy of breast and lung cancer  is crucial and has to be confirmed for several breath-hold cycles that are needed for a SBRT session. Depending on the PTV size, the beam-on time for SBRT typically varies between 2 and 5 min, despite already higher dose rates obtained by omission of the commonly used flattening filter . Reprodug cancer , 14.Nevertheless, only limited data on SGRT and DIBH for SBRT is available. Here, we present our initial experience in utilizing a combination of SGRT and IGRT for patient positioning and treatment monitoring during SBRT of lung and liver targets.Ten patients transferred for lung or liver SBRT to our department in 2018/19 were included in this pilot study. Only patients who could hold their breath for at least 30 s were eligible for study inclusion. All patients gave informed consent for an individualized SBRT approach using DIBH instead of treatment in free-breathing and abdominal compression which is standard of care. For monitoring of correct DIBH reproducibility the hard- and software tools of Vision RT Ltd.  were used. These commercial solutions are officially approved and licensed for this purpose. The analysis was approved by the local ethics committee (S-063/2019).TM, Innovative Technologie Völp (IT-V), Innsbruck, Austria). The edges of the cushion near to the target area were folded and smoothed to prevent shadowing and concealment of parts of the body surface for appropriate optical surface-guidance. Abdominal compression was not used to mitigate free breathing motion as it would prevent DIBH, recognition of the body surface by shadowing and could potentially modify the patient’s surface in an unreproducible manner. The AZ-733V Respiratory Gating System  was utilized for registration of breathing motion and recording of time resolved, four-dimensional (4D) CTs. After 4D-CT acquisition, the respiratory belt was unstrapped and additional CT series in free-breathing as well as DIBH were recorded.Planning simulation was performed for all patients in vacuum cushion immobilization . Target volumes were delineated using available contrast-enhanced imaging in both free-breathing and DIBH sequences. Planning target volumes (PTV) were generated in DIBH by adding a 3–5 mm safety margin to the clinical target volume (CTV). The CTV was created from the gross tumor volume (GTV) with an isotropic margin of 5–7 mm to account for microscopic spread. In contrast, the free-breathing PTV was created by a 2–3 mm expansion of an internal target volume (ITV) that integrated all motion information of the CTV extracted from the 4D-CT data. Treatment plans were calculated for both DIBH and free-breathing PTV, with the latter prepared as a precautionary measure in case of technical issues or patient-related problems with breath-hold.TM version 5.1.1, Vision RT, London, United Kingdom) used for DIBH positioning and monitoring is shown in The SBRT workflow of this study incorporates positioning and monitoring of patients in DIBH with surface-guidance . A screeIn brief, the software allows for accurate patient set-up in DIBH and a radiation-free real-time feedback of DIBH positioning during the treatment session. Reproducibility of DIBH position was validated in-room by one to two repetitions. To verify the surface-guided position, a fast cone-beam computed tomography (CBCT), which lasts a breath-hold of 30 s, was acquired in DIBH. After registration to the planning CT, the couch was moved in DIBH accordingly and this new image guided position directly captured as a new surface reference in the SGRT software. To validate the reproducibility of tumor position in different breath-hold sequences, an additional fast CBCT was acquired. If a new registration resulted in shifts >2 mm, the couch was moved in DIBH as needed and the reference surface updated. Finally, orthogonal 2D-MV portal imaging was acquired in DIBH to confirm correct isocenter positioning.After correct patient positioning the treatment was delivered in DIBH by a linear accelerator  using a flattening filter free (FFF) technique to reduce beam-on time whenever possible. We decided to set the individual defined region of interest (ROI), for which the SGRT software calculates differences in patient’s actual surface and the reference surface, to the lower thorax to measure thoracic motion during DIBH and to avoid large distances between the treatment isocenter and the ROIs’ centroid in liver SBRT. During treatment delivery the maximum allowed position error was 3 mm and 2° for translational and rotational differences, respectively. For patients’ comfort the treatment delivery was also stopped every 20–40 s to allow for breaks and prevent patients from becoming out of breath. The overall treatment time including positioning and IGRT varied between 20 and 60 min depending on various patient specific factors concerning breath-hold  resulting in different numbers of breath-holds needed.Differences in couch coordinates were assessed during the course of daily CBCT imaging  and compared to the derived shifts from subsequent treatment days . For each patient and CBCT, a static, breathing-independent anatomic landmark (mostly Schmorl’s nodes or enostosis of the spine at the level of the gross tumor) and a moving, breathing-dependent landmark (such as clips near the liver target lesion or a pulmonary vessel branching adjacent to the lung target lesion) were defined and their intra- and interfractional positions compared.p-value was less than 0.05. D’Agostino and Pearson omnibus K2 normality tests suggested a Gaussian distribution for the continuous variables of the vector length of position correction and spatial distance of fix and moving points, gross tumor volumes (GTV) and planning target volumes as well as the differences in planning target volumes in free-breathing and in DIBH for the same patient. Statistical differences between volumes of lung and liver targets were assessed using unpaired t-tests with Welch correction (Welch t-tests), which are more reliable for populations with unequal sample sizes and different variances than Student’s t-test. Paired t-tests were conducted for comparison of PTVs in DIBH and in free-breathing of the same patients. Frequencies of needs for a second position correction were grouped by target location and analyzed in a 2 × 2 contingency table and differences analyzed using Fisher’s exact test.Prism 7.04 software  was used to perform statistical analysis and graphical plotting of results. Results were considered significant when the two-tailed As a proof of concept analysis, we performed SBRT in DIBH in a total of 10 patients and for 41 treatment fractions using a combination of CBCT image- and surface-guidance for position verification and monitoring of DIBH. Details of our workflow are depicted in y-axis  and 8.8 mm (1.7–26.9) for lung and liver targets, respectively. Compared to liver targets, the correction vectors of lung targets were significantly smaller .A second position verification by CBCT in DIBH utilizing the newly captured reference surface could confirm a correct set-up in most cases. A new couch shift was required in 1 of 9 (11%) and 7 of 34 (21%) treatment sessions for lung and liver targets, respectively. Despite higher rates for liver SBRT, there was no significant difference in the frequency of the need for a second position correction for lung and liver targets . Equality of distances of first and second CBCT as well as of planning CT and first CBCT would correspond to no intra- and no interfractional difference, respectively.p = 0.12, Welch’s t-test).Intra-fraction distances of both lung and liver targets were close to the line of equality . On averp = 0.01, Welch’s t-test), indicating higher variability between treatment sessions for liver SBRT compared to lung SBRT.In contrast, mean interfractional differences for lung targets were 0.9 mm , whereas in liver targets the average difference was 3.8 mm (−32.7 to 13.8) with a higher IQR of 6.8 mm . These ip = 0.018, Welch’s t-test). The mean internal target volumes (ITV) which comprise the clinical target volumes (CTV) with additional margins obtained from 4D-CT data in free-breathing was 108 ml for all lesions. By using DIBH these margins could be omitted and the CTV in DIBH was 28% smaller . This reduction of target volumes by using DIBH was seen for both lung and liver targets. However, statistical significance was not reached for the smaller sub-group of lung targets (The mean gross tumor volumes (GTV) of lung targets, liver targets and all lesions were 1.9, 67, and 48 ml, respectively, with significantly smaller GTVs for lung targets , a commercial device consisting of a nose clamp and a mouthpiece that is connected to a breathing tube containing a valve which closes once a pre-defined target air volume is inhaled by the patient. The prospective United Kingdom HeartSpare Study compared this ABCTM-assisted breath-hold with a voluntary breath-hold technique and found that the latter was non-inferior in terms of reproducibility and normal tissue sparing. Moreover, voluntary breath-hold was faster and preferred by both patients and therapists  on the patients’ body surface and a corresponding reference surface generated from the external contour of the planning simulation CT, facilitating a fast and accurate patient set-up with six degrees of freedom . SGRT isFor SBRT in targets that move with respiration, an abdominal compression is traditionally employed to mitigate breathing motion and to decrease the residual range of motion, as assessed during time resolved CT acquisition. These 4D-CT data are used to create a PTV that encompasses the tumor during the entire breathing cycle or to define a specific gating window which results in reduced irradiation volumes but, on the other hand, extend treatment delivery time , 20. MorEarlier data on SGRT and SBRT in free-breathing suggests that the pre-imaging treatment set-up for SBRT can be improved by SGRT compared to in-room laser localization of skin tattoos or skin marks . MoreoveWe observed highest interfractional variability in cranio-caudal direction and lowest in left-right direction, underpinning the idea that respiratory motion, which is mostly performed by the diaphragm, impacts most on target localization. Indeed, using SGRT for positioning of breast cancer patients in free-breathing showed least errors for lateral set-up compared to imaging . Our datTM)-controlled breath-hold for lung and liver SBRT reported good intrafractional reproducibility of liver position in the majority of patients. However, interfractional reproducibility was worse, suggesting a need for daily image guidance (TM-controlled breath-holds to be <2 mm and <5 mm in 59 and 95% of 385 DIBHs in 13 patients (Previous work on employing active breathing coordinator (ABCguidance –33. Anotguidance . This inpatients .The most elegant solution for precise and accurate SBRT in DIBH is probably possible with MR-guidance since on-board magnetic resonance (MR) imaging in linear accelerators (MR-LINAC) for set-up and treatment delivery is non-invasive, exposes the patient to no additional radiation and allows for direct target localization and real-time visualization . In contSurface-guided radiotherapy in DIBH for lung and liver tumors using a combination of SGRT and IGRT is feasible. This approach is easy to incorporate in contemporary practice and does not require any breathing tubes connected to the patient. Nevertheless, daily 3D imaging is of paramount importance given that interfractional variability is high, particularly in DIBH for liver SBRT.The datasets presented in this article are not readily available because legal regulations disallow and as a requirement of local ethics committee clinical raw data must not be made available to others than those involved in the study. Requests to access the datasets should be directed to patrick.naumann@med.uni-heidelberg.de.The studies involving human participants were reviewed and approved by Ethikkommission Heidelberg. The patients/participants provided their written informed consent to participate in this study.PN and VB were responsible for conceptualization, data curation and formal analysis. BR and JD supervised the project. PN drafted the manuscript. PN, VB, JF, BR, and ET-M participated in patient treatment. BF and JL critically reviewed the manuscript. All authors read and approved the final manuscript.In the past 5 years JD attended advisory board meetings of MERCK KGaA (Darmstadt), for which the University hospital Heidelberg received travel grants and honoraria. His department further received funding for research projects and for educational grants to the University hospital of Heidelberg by Accuray (2016), Merck KGaA (2015-open), Siemens GmbH (2015-open), Viewray (2018-open), Vision RT (2017-open). He is CEO of the HIT GmbH and also member of the kuratorium of the Physikalisch Technische Bundesanstalt (PTB). As chair of HIRO (Heidelberg Institute of Radiation Oncology) and director of the NCT  he is responsible for collaborations with a multitude of companies and institutions. JD confirms that to the best of his knowledge none of the above funding sources was involved in the data analysis and preparation of this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Downloading a COVID-19 contact tracing app may be effective in reducing users’ worry about COVID-19 and psychological distress.This 2.5-month prospective study aimed to investigate the association of downloading a COVID-19 contact tracing app, the COVID-19 Contact Confirming Application (COCOA), released by the Japanese government, with worry about COVID-19 and psychological distress in a sample of employed adults in Japan.A total of 996 full-time employed respondents to an online survey conducted May 22-26, 2020 (baseline), were invited to participate in a follow-up survey August 7-12, 2020 (follow-up). A high level of worrying about COVID-19 and high psychological distress were defined by baseline and follow-up scores on a single-item scale and the Kessler 6 (K6) scale, respectively. The app was released between the two surveys, on June 17. Participants were asked at follow-up if they downloaded the app.A total of 902 (90.6%) of 996 baseline participants responded to the follow-up survey. Among them, 184 (20.4%) reported that they downloaded the app. Downloading of the contact tracing app was significantly negatively associated with psychological distress at follow-up after controlling for baseline variables, but not with worry about COVID-19.This study provides the first evidence that using a government-issued COVID-19 contact tracing app may be beneficial for the mental health of employed adults during the COVID-19 pandemic. Contact tracing is one of the most effective methods of controlling infectious diseases. During the 2020 COVID-19 pandemic, many smartphone apps for digital contact tracing have been developed and widely used . These cThis prospective study aimed to examine the effect of the use of a COVID-19 contact tracing app released by the Japanese government in mid-June 2020 on the perceived threat from COVID-19 and psychological distress in a sample of employed adults in Japan. We examined the association between reported use of the COVID-19 contact tracing app and worry about COVID-19 and psychological distress at follow-up, adjusting for these variables at baseline.This study was a 2.5-month prospective study with two consecutive online surveys. Participants responded to an online “closed” survey conducted May 22-26, 2020 (baseline), which was part of a larger longitudinal study of full-time employees aged 20-59 years that were recruited by an internet survey company (Macrimill Inc) from a large pool  of self-selected preregistered community-dwelling residents across Japan ,12. AfteOn June 19, 2020, the Japanese government released a free contact tracing app for COVID-19, called the COVID-19 Contact Confirming Application (COCOA), for iOS and Android . The appWe used a single-item scale to measure worry about COVID-19 at baseline and follow-up, by asking “Do you worry about COVID-19?” and using a 6-point Likert-type response scale ,12. The Psychological distress (depression and anxiety) in the last 30 days was measured using the Kessler 6 (K6) scale  at baselParticipants were asked their sex , age , marital status (currently married or not), educational attainment (high school graduate and lower or university graduate and higher), and occupation ; whether they work from home , live with a child up to high school age (yes or no), or live in high-risk areas designated during the COVID-19 emergency between April and May 2020 by the government (yes or no) [P<.05. SPSS  was used for analyses.The adjusted prevalence of worry about COVID-19 and high psychological distress at follow-up (controlling for baseline levels) were compared between those who did or did not use the COVID-19 contact tracing app (Mantel-Haenszel chi-square test). Multiple logistic regression analyses were conducted to estimate the effect (odds ratio [OR] and 95% CI) of worry about COVID-19 or high psychological distress at follow-up, adjusting for the baseline demographic variables and baseline values of these variables. No weighting was made to adjust for the nonrepresentativeness of the sample. Statistical significance was set at Online informed consent was obtained from all participants with full disclosure and explanation of the purpose and procedures of this study. We explained that their participation was voluntary, and that they could withdraw consent for any reason, simply by not completing the questionnaire. This study was approved by the Research Ethics Committee of the Graduate School of Medicine/Faculty of Medicine at The University of Tokyo [number 10856-(2)(3)(4)(5)].A total of 902 (90.6%) of 996 participants at baseline responded to the follow-up survey. Among them, 184 (20.4%) reported that they downloaded the app. The respondents who downloaded the app were significantly more likely to be male, older, living with a child, university graduates or higher, and working from home than respondents who did not download the app . PrevaleP=.02). Downloading of the contact tracing app was significantly negatively associated with psychological distress at follow-up in the group without high psychological distress at baseline . Downloading of the app was significantly negatively associated with psychological distress at follow-up after adjusting for all covariates .Downloading of the app was significantly negatively associated with psychological distress at follow-up after adjusting for psychological distress at baseline  or after adjusting for all covariates .We conducted these multivariate analyses using age with a different categorization  and as a continuous variable, and obtained similar findings. When using the alternative definition of severe psychological distress , downloading of the app was not significantly associated with severe psychological distress at follow-up  and reduce their psychological distress, even though they still worry.A contact tracing app decreased the prevalence of mild psychological distress by 7.4 points on average . The effect size was rather small, but it might have a large impact on mental health (which has been reported to have deteriorated during the pandemic ) becauseWhile the app certainly provides users with objective information about the risk of COVID-19 infection, participants’ worry about COVID-19  was not different at follow-up between users of the contact tracing app and nonusers. In fact, the number of notifications that users had been in contact with a COVID-19–positive person was very limited  . The effAlthough this study indicated a possible benefit to mental health related to using a contact tracing app, there are other issues to be considered before encouraging the use of the app . There aFirst, although the study employed a prospective design, downloading of the contact tracing app was measured at follow-up. Thus, the direction of causality between use of the app and psychological distress is unclear; it is conceivable that participants whose mental health has improved are more likely to start using the app. In addition, users had to complete a few steps after downloading the app to approve the use of the app and allow it to access the Bluetooth function. Thus, downloading the app may not necessarily be equal to use of the app. Some may have uninstalled the app soon after they downloaded it. Research using a more accurate assessment of the use of the app is needed to confirm our findings. Second, we investigated the effect of a government-released contact tracing app in this study. The findings may not be applicable to similar contact tracing apps released by commercial entities, which may be less trusted by people than government-released ones. Third, because the study sample included only employees, and might be demographically biased in some other way, the findings may not be generalizable to the general population . The prevalence of psychological distress in this sample (40%-50%) was slightly higher than that reported in previous studies (34%-38%) . The samThis prospective study found that downloading of the COVID-19 contact tracing app released by the Japanese government was significantly negatively associated with psychological distress in a sample of employed adults in Japan. Downloading of a COVID-19 contact tracing app may reduce psychological distress among users during the COVID-19 pandemic. However, other ethical and psychological issues related to contact tracing apps need to be fully discussed and resolved before recommending the app to public health officials.


To the Editor,The current pandemic that has paralyzed the world economy is caused by a new coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)]. Although the lung is a major target organ of the virus, it can also strike other parts of the body including the nervous system. Neurologic presentations of COVID-19 are ranging from nonspecific and moderate to severe. Most patients have mild symptoms like headache and make a good recovery. However, a minority of patients develop severe complications with unfavorable outcomes including cerebrovascular diseases [SARS-CoV-2 is considered novel because of its special features. But simultaneously, there are similarities between this and other betacoronaviruses. For instance, genomic analysis indicated that Middle East respiratory syndrome coronavirus and SARS-CoV share high degrees of sequence homology with SARS-CoV-2. Moreover, SARS-CoV and SARS-CoV-2 use the same host receptor for cell entry [Neurotropic and neuroinvasive properties of SARS-CoV-2 are supported by several observations including the presence of virus particles in the cerebrospinal fluid of patients with significant nervous system symptoms .Currently, it is difficult to distinguish whether neurological complications of COVID-19 are a consequence of direct or indirect effects of viral infection. However, existing data highlight the importance of considering both effects.Direct effects may occur by multiple mechanisms including viral transit across the cribriform plate or olfactory bulb to brain. Another mechanism relies on blood circulation and angiotensin-converting enzyme 2 (ACE2) receptors that are expressed on glial cells, neurons, and capillary endothelium and are involved in virus entry .In addition to direct adverse consequences, several indirect mechanisms have been proposed to account for neuropathologic properties of SARS-CoV-2. For instance, viral replication within the lung pneumocytes may lead to hypoxic conditions and gas exchange disorders in the nervous system. Another mechanism appears to be related to ACE2 which acts as a cardiocerebral vascular protection factor and plays an important role in blood pressure regulation and antiatherosclerosis mechanisms. Virus binding to ACE2 receptors can lead to hypertension and increase the risk of ischemic stroke and cerebral hemorrhage , 4.The third indirect mechanism is linked to the host immune response against virus. Some evidence indicates that neurological symptoms of COVID-19 could be induced by uncontrolled production of cytokines. These mediators are produced by different cells including glial cells.The ability of these cells to produce proinflammatory cytokines has also been demonstrated in experimental models, after corona virus infection . MoleculAltogether, the nervous system may be affected by SARS-CoV-2. Neurological manifestations related to the virus are varied and complex. Therefore, understanding of neural pathways that contribute to neurologic deficits can be beneficial in promoting assessment and management of COVID-19 patients.


NLRP3 gene is associated with autosomal-dominant sensorineural hearing loss with cochlear autoinflammation in two unrelated families. NLRP3 encodes the NLRP3 protein, a key component of the NLRP3 inflammasome that is expressed in immune cells, including monocytes and macrophages. Gain-of-function mutations of NLRP3 cause abnormal activation of the NLRP3 inflammasome leading to IL-1β secretion in a spectrum of autosomal dominant systemic autoinflammatory phenotypes termed cryopyrin-associated periodic syndromes. The affected subjects of our two families demonstrated atypical phenotypes compared with those reported for subjects with cryopyrin-associated periodic syndromes. These observations led us to test the hypothesis that macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The inflammasome can indeed be activated in macrophage/monocyte-like cells of the mouse cochlea, with secretion of IL-1β. The macrophage/monocyte-like cells in the cochlea were also found to be associated with hearing loss in a Slc26a4-insufficient mouse model of human deafness. This review addresses our understanding of genetic hearing loss mediated by autoinflammation and macrophage/monocyte-like cells in the cochlea.Sensorineural hearing loss can result from dysfunction of the inner ear, auditory nerve, or auditory pathways in the central nervous system. Sensorineural hearing loss can be associated with age, exposure to ototoxic drugs or noise, or mutations in nuclear or mitochondrial genes. However, it is idiopathic in some patients. Although these disorders are mainly caused by dysfunction of the inner ear, little of the pathophysiology in sensorineural hearing loss is known due to inaccessibility of the living human inner ear for biopsy and pathological analysis. The inner ear has previously been thought of as an immune-privileged organ. We recently showed that a missense mutation of the  Sensorineural hearing loss can result from dysfunction of the inner ear, auditory nerve or higher auditory pathways in the central nervous system. Sensorineural hearing loss includes a wide variety of disorders, such as idiopathic sudden sensorineural hearing loss, age-related hearing loss, hearing loss associated with exposure to ototoxic drugs or noise, and almost all heritable forms of non-syndromic hearing loss. Although these disorders are usually caused by dysfunction of the inner ear, the pathophysiology in sensorineural hearing loss is usually unknown due to inaccessibility of the living human inner ear for biopsy and pathological analysis.NLRP3 mutation. We also review the role of cochlear macrophages in a mouse model of genetic hearing loss phenotypes, non-syndromic recessive deafness DFNB4 and Pendred syndrome, caused by variants of the SLC26A4 gene.In this review, we focus on the hearing loss caused by dysregulation of the NLRP3 inflammasome. The NLRP3 inflammasome is a critical component of a widely studied, canonical inflammatory signaling pathway in the innate immune system. We review syndromic and non-syndromic hearing loss phenotypes caused by an NLRP3 gene  encodes the NLRP3 protein , a key and eponymous component of the NLRP3 inflammasome . The CAPS spectrum includes three classical clinical subtypes: neonatal-onset multisystem inflammatory disease , Muckle-Wells syndrome , and familial cold autoinflammatory syndrome . These phenotypes share signs and symptoms including recurrent fever, rash, headache, conjunctivitis, and arthralgia or arthritis. All of the CAPS subtypes include serologic evidence of systemic inflammation.Gain-of-function mutations of NLRP3 mutations lead to CAPS via constitutive activation of the NLRP3 inflammasome and increased IL-1β production  in a North American Caucasian family (LMG113)  in (LMG113) . There wNLRP3 also causes sensorineural hearing loss with mixed signs and symptoms of systemic autoinflammation in affected members of an unrelated North American family, LMG446, of mixed Caucasian and Hispanic ancestry  mutation of Three affected members of family LMG446 were treated with subcutaneous anakinra. After 5 months of therapy, the pure-tone audiometric thresholds of two members were completely within normal limits . The. TheCx3cmembrane . These GNlrp3 is expressed in cochlea-resident cells expressing Cx3cr1 , we measured levels of IL-1β in supernatants of cultured wild-type mouse cochlear tissues. Higher levels of IL-1β were secreted from cultured cochleae stimulated with LPS and ATP, in comparison to cochleae cultured with LPS but not ATP (mulation . Mature in vivo (The stria vascularis is located in the lateral wall of the cochlea and is composed of three layers of cells: marginal cells, intermediate cells, and basal cells. The stria vascularis contains an extensive vascular network that is physiologically compartmentalized from surrounding strial cells by the blood-labyrinth barrier. The blood-labyrinth barrier includes a layer of endothelial cells connected by tight junctions within the walls of strial blood vessels. The stria vascularis produces endolymph and generates the endocochlear potential that is required for inner ear sensory hair cell function. The normally functioning tight junction-based blood-labyrinth barrier is believed to prevent or restrict the diffusion of immune cells, inner ear antigens, and antibodies between the circulation and the strial tissue , 27. Macin vivo .Slc26a4-null mouse, a model of Pendred syndrome (Slc26a4-insufficient mouse with fluctuation of hearing and endocochlear potential (Cd68 mRNA levels. These data support the hypothesis that macrophage activity is affecting hearing by influencing the function of the stria vascularis. Additionally, we observed that macrophages appeared to phagocytose pigment granules, which are increased in the stria vascularis of Slc26a4-insufficient cochleae (Slc26a4-insufficient cochlea remain undetermined. However, similar observations were reported for macrophages in the iris and ciliary body of the anterior chamber of the eye, presumably to ensure excess pigment granules are retained in the tissue and not released into the anterior chamber of the eye (The origin of the perivascular macrophages in the normal resting stria vascularis is controversial , 31. Howotential . The areotential . Also, tcochleae . The rol the eye .NLRP3 can cause non-syndromic sensorineural hearing loss as well as an atypical presentation of CAPS. In wild-type mouse cochlea, the NLRP3 inflammasome exists and can be activated in the macrophages. These results support the hypothesis that local cochlear activation of the NLRP3 inflammasome can induce cochlear autoinflammation and sensorineural hearing loss in the affected subjects. In an Slc26a4-insufficient mouse model of sensorineural hearing loss, macrophage activity is likely affecting hearing by influencing the function of the stria vascularis. Thus, macrophages in the cochlea can affect cochlear and auditory function in more than one disorder and, possibly, in many disorders of hearing.Macrophage-like cells are scattered throughout all cochlear tissues, including the auditory nerve, spiral ganglion, basilar membrane, stria vascularis, and spiral ligament. The p.Arg918Gln mutation in All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The coronavirus disease 2019 (COVID-19) pandemic resulted in an unprecedented expansion in telehealth, but little is known about differential use of telehealth according to demographics, rurality, or insurance status.We performed a cross-sectional analysis of 7742 family medicine encounters at a single USA institution in the initial month of the COVID-19 public health emergency (PHE). We compared the demographics of those using telehealth during the PHE to those with face-to-face visits during the same time period; we also compared the demographics of those using full audio-video to those using audio-only.The likelihood of any telehealth visit in the first 30 days of telehealth expansion was higher for women, those age 65 years and older, self-pay patients, and those with Medicaid and Medicare as primary payers. The likelihood of a telehealth visit was reduced for rural residence and Black or other races. Among all telehealth visits, the likelihood of a full audio-video telehealth visit was reduced for patients who were older, Black, from urban areas, or who were self-pay, Medicaid, or Medicare payer status.Significant disparities exist in telehealth use during the COVID-19 PHE by age, race, residence and payer. Under the National Emergency declaration,511 Prior to the COVID-19 pandemic, the adoption of telehealth was slowed by payment constraints, provider concerns and organizational barriers.12 Additionally, disparities in access to and use of telehealth services existed across demographic and socioeconomic strata. For example, among insured patients, those who are employed and have post high-school education had higher uptake of telehealth services.13 Among residents of rural communities, patients who utilized telehealth visits were more likely to be white and non-Hispanic,14 younger,15 have insurance16 and live in a poorer community.15 Studies of telehealth associations with race and rurality had mixed results.17 This earlier research has evaluated telehealth use prior to the COVID-19 telehealth expansion, and little is known about telehealth use following the onset of the pandemic. To address these knowledge gaps, we conducted a cross-sectional analysis of primary care patients who utilized telehealth visits during the first 30 days after the expansion of telehealth services during the COVID-19 pandemic. We investigated potential disparities in telehealth use according to demographic , rurality and insurance payer subgroups.Telehealth is effective and generally satisfies patients’ care expectations.c. 800,000 people. The Department of Family and Community Medicine provides much of the primary care to the core of this region, with 89 clinicians based in seven outpatient practices across three different counties. Following the CMS announcement of expansion of telehealth under the national emergency 1135 waiver,2 MU Health implemented several procedural and administrative policies for telehealth visits, including (a) obtaining consent for telehealth; (b) conventions for titling medical documentation to reflect whether the visit was full telehealth (audio and video) or audio-only; (c) a requirement that providers document the duration of audio-only visits; and (d) a new distinct appointment type in the practice management software for telehealth encounters. This retrospective analysis included all finalized ambulatory clinic encounter documentation (‘Family Medicine Clinic Note’) completed by residents, attendings and advanced practice providers providing primary care in the Department of Family and Community Medicine. Encounter documentation during the first 30 days of the COVID-19 pandemic (17 March to 16 April 2020) was included. Visits with only operative notes were excluded. Scheduled visits to which the patient did not arrive and were not charged were excluded. Patient demographics were extracted directly from the MU Health Center electronic health record (EHR) database. Encounter data were determined based on administrative claims coding. Demographics were compared to similar population from the same practice sites and the same 30-day period in 2019.We conducted an analysis based on telehealth utilization during the COVID-19 pandemic at a single academic centre in the USA , the only academic medical centre in central Missouri, serving approximately 25 counties with a population of 18 Encounters were classified as audio-only telehealth if charge data supported either virtual check-in  or telephone evaluation and management visits (99441–99443). In some cases, charge data was incomplete due to delays in note completion. In these cases, authors determined visit type based on data extracted from individual charts and using the telehealth note titling and time documentation conventions established in health-system policy. Sex, race and ethnicity were self-reported. Insurance status was determined by primary payer listed on corresponding visit. Medicare Advantage plans were classified as private insurance. Rurality was assigned based on patient postal codes according to the Federal Office of Rural Health Policy.19Encounters with charges for services associated with a telehealth appointment type were classified as telehealth.t-test with Welch’s approximation were used for comparisons where appropriate.In order to determine how representative the study encounters were and how the demographics of patients compared to a non-pandemic year, demographics, rurality and payer status for patients with visits in the first 30 days of the COVID-19 telehealth expansion were compared to those with visits from the same 30-day period in 2019. Chi-square Student’s p-value of 0.05 was considered statistically significant. Statistical analysis performed using Stata/IC v16.0 . Patients with missing data were excluded from the logistic regression analysis. This study was reviewed by the University of Missouri Institutional Review Board and determined to be exempt, and informed consent was not separately obtained for this retrospective analysis.For all encounters during the COVID-19 telehealth expansion, likelihood of telehealth visits versus in-person encounters were determined using multivariate logistic regression models adjusted for sex, age , race , ethnicity  rurality , payer status categories . For the telehealth encounters, likelihood of full audio-video telehealth encounters versus audio-only encounters was determined by estimating a multivariate regression model using the same variables. A The initial analysis included 7891 encounters during the first month of the COVID-19 telehealth expansion. Fifty-six were excluded as operative encounters, and 93 were excluded because the patient either never arrived or no charges were billed. Final analysis included 7742 encounters representing 6984 unique patients . Over thp = 0.002), Black , Hispanic . The distribution of payers also differed between 2020 and the prior year, with a somewhat higher percentage of encounters during the COVID-19 emergency among patients with Medicaid and without insurance  was lower among those aged 45–64  and 65 years and older . Full audio-video telehealth was also less likely among Blacks  compared to whites and patients with Medicaid , Medicare , or self-pay , compared to private insurance. Among the telehealth encounters, full audio-video was more common among those with rural residence  compared with urban .Our findings demonstrate several disparities in the use of telehealth during the COVID-19 telehealth expansion. Relative to the prior year, men, whites and non-Hispanics were less likely to be seen by any method, although the clinical significance of these small differences is unclear. During the COVID-19 public health emergency (PHE), telehealth visits were used more often by women, older patients, and those with Medicare, Medicaid, and self-pay status. Telehealth was used less often by those of non-white race and those from rural postal codes. Among those seen using telehealth, younger patients and those from a rural postal code were more likely to utilize full audio-video capability, and phone-only visits were more frequent with older patients, Blacks, and those with Medicaid, Medicare, and self-pay status. Ours is among the first studies to describe these disparities in telehealth use since the start of the COVID-19 pandemic.17 In our population, patients were more likely to utilize telehealth visits with increasing age during COVID-19 telehealth expansion, suggesting that the COVID-19 pandemic might have alter previous patterns of telehealth uptake. Higher rates of telehealth may be due to greater fear of contracting COVID-19 among older persons and the subsequent desire to quarantine and maintain social distance. Despite higher rates of telehealth visits, older patients were less likely to utilize full audio-video visits. A full audio-video telehealth visit requires a computer or mobile device and willingness and ability to download and use new software. Older patients are less likely to access the internet20 and use smartphones21 and health-information technology,22 likely contributing to higher rates of audio-only encounters.Our findings differ from a recent study of telehealth use prior to the COVID-19 pandemic, which demonstrated lower telehealth use with increasing age.23 In work done prior to the COVID-19 pandemic, large studies evaluating the relationship between telehealth use and race have yielded conflicting results.17 In our work, Black patients represented a greater proportion of encounters during the COVID-19 telehealth expansion compared to the same period prior year. During those COVID-19 period encounters, Black patients were less likely to use telehealth, and when telehealth was used, it was more often limited to audio capabilities alone. Despite previously conflicting evidence, our work suggests significant racial disparities in telehealth use during the COVID-19 PHE. These disparities may lead to worsening of existing racial disparities for health outcomes among racial and ethnic minority populations.Race and ethnicity are known to have a significant impact on COVID-19 incidence and mortality.24 None of these known associations explains our findings in the first 30 days of the COVID-19 telehealth expansion. Further research is needed to clarify the relationships between rural residence, distance from services, broadband coverage and telehealth use during the COVID-19 pandemic.Surprisingly, rural residents were less likely to engage in telehealth encounters in our study, but more likely to use full audio-video capability. Rural residents have fewer healthcare services, fewer trained physicians and worse broadband coverage.25 and previous studies have associated low socioeconomic status with lower healthcare utilization.27 Our findings were mixed in this regard. Compared to the prior year, Medicaid and self-pay patients were less likely to reduce their healthcare utilization during the public-health emergency, and encounters for patients without insurance actually increased. The significance of and reasons for this finding are unclear but may reflect less perceived capacity to self-manage health conditions during the early phases of the pandemic. During the COVID-19 telehealth expansion, compared to patients with private insurance, patients with government payers and self-pay status had relatively higher odds of a telehealth encounter. It is not surprising that, compared to those covered by private insurance, telehealth encounters were more likely to be audio-only among those with government payer or with self-pay status, as those patients may be less likely to have the mobile devices and computers required for full audio/video telehealth.Payer status serves as a proxy for socioeconomic statusTaken together, our findings reflect disparities in patients’ responses to the COVID-19 PHE. Telehealth is clinically effective and satisfying for patients to use. Further research should focus on the effect of these changes and disparities on downstream health outcomes, patient satisfaction, healthcare costs and interventions which might address inequities. Additional focused, community-engaged interventions may be needed to ensure equitable access to telehealth services in primary care settings during the COVID-19 PHE.28 providers who care for a disproportionate number of older, Black, Medicaid, or self-pay patients would have been disadvantaged financially. An increase in the use of telehealth will likely persist after the resolution of the COVID-19 pandemic,29 so reimbursement policies in the post-emergency period will need to account for these disparities.Our findings also have important implications for reimbursement policy in the USA. Initial telehealth reimbursement rates for telephone visits were substantially lower than for full audio-video telehealth encounters. While policy changes later rectified these inequities,Our study should be interpreted in the context of several limitations. Our study was performed during a disruptive period for patients and providers and may not reflect longer term patterns of telehealth use. This population of patients in central Missouri may underrepresent certain race, ethnicity and socioeconomic groups. ‘Rural’ as defined by FORHP postal code data and used in this study does not fully represent the spectrum of rurality in the USA. We only examined patient encounters and did not include appointments that were cancelled or not kept. A more complete portrait of the COVID-19 telehealth expansion would account for this activity. The chronic medical conditions for each patient were not evaluated and this is potentially a significant confounder. Finally, this study did not address clinical outcomes following telehealth visits, which is an important area for future research.Disparities exist in telehealth use by age, race, residence and payer in the period of telehealth expansion at the onset of the COVID-19 PHE. Further work is needed to clarify underlying causes these disparities and to inform policy-making during the COVID-19 emergency and beyond.