Brain synchronizations are orchestrated from neuronal oscillations through frequency interactions, such as the alpha rhythm during relaxation. Nevertheless, how the intrinsic interaction forges functional integrity across brain segregations remains elusive, thereby motivating recent studies to localize frequency interactions of resting-state fMRI (rs-fMRI). To this point, we aim to unveil the fMRI-based spectral interactions using the time-frequency (TF) analysis; however, Fourier-based TF analyses impose restrictions on revealing frequency interactions given the limited time points in fMRI signals. Instead of using the Fourier-based wavelet analysis to identify the fMRI frequency of interests, we employed the Hilbert–Huang transform (HHT) for probing the specific frequency contribution to the functional integration, called ensemble spectral interaction (ESI). By simulating data with time-variant frequency changes, we demonstrated the Hilbert TF maps with high spectro-temporal resolution and full accessibility in comparison with the wavelet TF maps. By detecting amplitude-to-amplitude frequency couplings (AAC) across brain regions, we elucidated the ESI disparity between the eye-closed (EC) and eye-open (EO) conditions in rs-fMRI. In the visual network, the strength of the spectral interaction within 0.03–0.04 Hz was amplified in EC compared with that in EO condition, whereas a canonical connectivity analysis did not present differences between conditions. Collectively, leveraging from the instantaneous frequency of HHT, we firstly addressed the ESI technique to map the fMRI-based functional connectivity in a brand-new AAC perspective. The ESI possesses potential in elucidating the functional connectivity at specific frequency bins, thereby providing additional diagnostic merits for future clinical neuroscience. The importance of brain science lies in the time-variant synchronization and desynchronization of neuron assemblies across space, forming dynamic regional oscillations over a wide range of frequency complexes. To date, several academic studies have discovered the importance of neural oscillations in daily life by demonstrating associations between electrophysiological components  on the basis of multi-type physiological states or cognitive processes. For example, a strong alpha-band 8–13 Hz) activity in electroencephalography (EEG) emerges during wakeful relaxation when the eyes are closed, whereas a gamma-band (>30 Hz) activity is associated with the genesis of behavior 3 Hz acti. ConventSpecific oscillation frequencies possess either physiological or cognitive inferences, and the emerging evidence indicates that cross-frequency  interactions between neuronal oscillations associate with distinct emotional states and cognitive processes ,11. For Since taking both temporal and spectral information into consideration could further reveal the underlying neurophysiological information of resting-state functional connectivity, one novel approach to achieve this goal is to perform the time-frequency (TF) analysis prior to the functional connectivity analysis. However, using the TF maps for functional connectivity analysis is not adopted in the rs-fMRI field because of the following two reasons: (1) compared with the broadband EEG signal spectrum 1–70 Hz), the fMRI hemodynamic responses contain only the ultra-low-frequency spectrum ; and (2) Fourier-based TF analyses are subject to the uncertainty principle. For the former part, indeed the low sampling rate of the fMRI signal constrains its frequency range within a low-frequency range technically, but the slow hemodynamic response function (HRF) automatically transforms the high-frequency neural oscillations into the low-frequency domain. Therefore, a series of studies reported that the low-frequency fMRI signal correlates with EEG signals across different frequency bands. Furthermore, Thompson et al. identified the specific frequency corresponding to brain connectivity efficiency 0 Hz, the. HoweverTherefore, for disclosing the high-resolution TF map of the rs-fMRI signal, we employed the HHT in this study to circumvent the restriction of the uncertainty principle. We applied the HHT to elucidate spectral interactions of the rs-fMRI signal on the well-addressed eye-closed (EC)/eye-open (EO) conditions. We hypothesized that the rs-fMRI signals in the visual network changed their frequency coupling between the EC and EO conditions. This statement holds true for the elevated alpha rhythm in the EC condition, which enables changes in spectral interactions derived from the fMRI TF maps. In this study, we first demonstrated that the resolution of the TF map generated using HHT outperforms that generated using wavelet transform. Next, we demonstrated the characteristics of spectral interaction with both the simulated and real fMRI data. Finally, we characterized the spectral interactions on the basis of HHT TF maps to detect conditional changes in frequency bands within the visual network. With the advantages of the high-resolution TF map, fMRI techniques have the potential to reveal cognitive functionality through spectral interactions within specific spatial locations in the brain.3 voxels without inter-slice gap]. To analyze the spectral interaction changes between the two conditions (EO/EC), a single-shot gradient-echo echo planar imaging (GE-EPI) sequence was adopted to acquire rs-fMRI data by using the following parameters: TR/TE = 2000/30 ms; flip angle = 90°; FoV = 220 mm; matrix size = 64 × 64; slice thickness = 3.4 mm; slice gap = 0 mm; 37 slices in total. Each EPI session contained 240 time points, equivalent to 8 min in acquisition. The scanning order of the EC/EO conditions was counterbalanced to reduce the systematic bias in rs-fMRI sessions. During the rs-fMRI sessions, the lights in the scanner room were turned off, and the participants were instructed to relax, stay awake, and not focus on anything in particular. Specifically, in the EC session, a black screen was presented to ensure that participants were exposed to dim light; they were instructed to keep their eyes closed throughout the scanning. In the EO session, a gray screen was presented; the participants were instructed to keep their eyes open and to look towards the screen. After scanning, participants were asked whether they had remained awake; none reported falling asleep.Fifteen right-handed, healthy volunteers  were enrolled in this study with the approval of the Institutional Review Board of Taipei Medical University (TMU-JIRB 201411043). The dataset was the subset of the normal control data in this clinical protocol and reused for technical development in this study. Informed consent was obtained from all subjects involved in the study prior to the examinations. Data were acquired with a 3 Tesla clinical scanner  by using a standard eight-channel head coil for signal detection and a whole-body coil for radiofrequency excitation. A high-resolution T1-weighted structural image was acquired using a 3D fast spoiled gradient-echo sequence (repetition time (TR)/echo time (TE) = 8.2/3.2 ms; flip angle = 8°; 193 slices with 1 × 0.88 × 0.88 mmAll scanning images were pre-processed using AFNI , FSL 2727, and STo successfully access the information on spectral interactions (cross-frequency coupling) from the fMRI signals with limited time points, an alternative approach is required to overcome the stationarity assumption and uncertainty principle inherited from the Fourier transform. Therefore, we implemented the HHT to extract physiological dynamics without the constraints of stationarity and linearity on the rs-fMRI signal. Unlike the Fourier transform, which uses the given mathematical basis, the HHT  method aTechnically, for mitigating the potential end effects and aliasing artifacts in Hilbert spectrum , the datAn illustrative comparison between the wavelet TF map and Hilbert TF map on a synthetic signal is presented in To demonstrate spectral interactions, we simulated two synthetic frequency-modulated waveforms. In each waveform, the signals changed frequency every 30 s twice within the 2-min duration. One signal was composed of 0.05-Hz and 0.07-Hz oscillations a, and thTo globally elucidate the characteristic of spectral interactions within the visual network, for each participant, we first selected 5 out of 30 ROIs from the visual network to generate a representative Hilbert TF map and then selected another 5 to generate another representative. Next, the aforementioned correlation analysis was conducted between the continuous temporal dynamics of the two representatives, resulting in an AAC map within the visual network. Moreover, to highlight the network changes between the EC/EO conditions and to reduce the variance of AAC maps, we randomly sampled the ROI subsets in the visual network ten times and averaged the findings to generate AAC maps, and then converted the values to Fisher z values to yield the ensemble spectral interaction (ESI) maps for each visual condition.t test with a paired sample design on ESI maps between the EC and EO conditions, and then corrected for multiple comparisons using the Bonferroni approach. Specifically, the ESI maps were first regridded to a size of 0.01 Hz by averaging their values per grid (resulting in 7 × 7 grids). Second, within each pair, the labels of the EC/EO conditions were randomly relabeled (swapped) to the regridded ESI maps of each individual. Third, a paired t test between the relabeled EC/EO ESI maps was performed to obtain a permutated t map. Forth, we performed five thousand permutations to create the permutated t distribution of the relabeled ESI maps between two conditions. Finally, the t map with the actual labeling between visual conditions was considered statistically significant if the two-tailed probability of the true t value in the permutated t distribution was higher than 97.5% or was lower than 2.5% . In contrast to ESI, we further examined the between-condition connectivity difference by using the canonical functional connectivity analysis (Pearson correlation) [To more accurately locate frequency-band alterations elicited by the condition changes, we applied a non-parametric permutation elation) , calculaTo examine the difference in spectral interactions between the EC and EO conditions in the visual network, we generated individual ESI maps in each resting-state condition. t test (EC-EO contrast) resulted in significantly higher spectral interactions within the frequency band of 0.03–0.04 Hz in the regridded ESI maps; however, it resulted in significantly lower cross-frequency interactions between frequency bands of 0.02–0.03 and 0.06–0.07 Hz (–0.07 Hz c (see Fip > 0.35) or those filtered by 0.03–0.04 Hz did not exhibit between-condition differences (p > 0.19) within the visual network  in the visual network. This observation proved the efficacy of this innovative method in localizing the spectral interactions given a pair of synchronous oscillatory signals. We performed the ESI using the following three steps: (1) decomposing fMRI signals through noise-enhanced EEMD, (2) conducting Hilbert spectral analysis to obtain TF maps, and then (3) conducting cross-correlation and collapsing the temporal information of the TF maps for obtaining spectral interactions at each frequency. Through this strategy, the aforementioned limitation for studying spectral interactions was completely prevented. First, by using the Hilbert TF map, we successfully disclosed that a certain fMRI spectrum (0.03–0.04 Hz) within 0.01–0.08 Hz contributed to the connectivity changes between the EC and EO conditions. Second, the ESI can be accomplished only because the Hilbert TF map provides spectral features without the PSF broadening and the COI restriction. Third, although ESI is a stationary index for frequency modulation , the Hilbert TF map disclosed the dynamic changes with full accessibility, revealing nonstationary TF information for further dynamicity studies. Most importantly, because HHT considers frequency and amplitude as functions of time separately without the constraint of the Fourier-based uncertainty principle, the Hilbert TF map does not possess the cone of influence (COI) limit in wavelet TF maps, which makes the implementation of ESI maps possible see . The othRs-fMRI fluctuations possess specific frequency features with neurophysiological mechanisms, which are the major objective of obtaining the spectral interaction map under low sampling rates and insufficient time points. Spectral interaction not only resembles the concept of functional connectivity by incorporating time curves from two regions to evaluate their mutual relation, but also provides frequency details. ESI maps extract the frequency information on the basis of high-resolution TF maps obtained using Hilbert-spectrum analysis. By collapsing the timing information of two simultaneously recorded signals, ESI maps denote the detailed correlation in the frequency domain. This is possible on the basis of Hilbert transform, because the Fourier-based methods  are affected by the uncertainty principle, particularly vulnerable in low-frequency components. However, two intrinsic properties of the ESI method shall be noticed for further applications. First, the Hilbert spectrum outputs the envelope amplitude for every frequency carrier in the TF map, instead of the raw amplitudes in the time curves. Therefore, unlike conventional correlation analyses for counting carrier fluctuations, the ESI map represents the correlation between enveloped amplitudes irrespective of the carrier frequency. Therefore, the ESI map denotes the AAC across different frequency carriers, which was also known as the frequency modulation in the communication principle  also sh. Second,When we close our eyes, a series of physiological phenomena occurs: a high density of alpha waves emerges from the synchronizations of neuronal populations and becomes detectable in the occipital lobes ; subsequIn this study, we implemented the Hilbert spectrum to highlight the time-variant frequency shifting. However, several problems must be addressed when HHT is applied to fMRI signals. First, because of the average process of IMFs in EEMD, one frequency signal may possibly be split into different IMFs, reducing its physiological significance for an individual IMF and thus resulting in misinterpretation of the results . To solvWe identified several considerations and limitations in the present study. First, instead of selecting spectral power, we used spectral amplitude for referencing the widely adopted unit in verifying functional characteristics of the cross-frequency coupling ,11,33,47We proposed an innovative HHT-based ESI method for investigating the frequency-specific interaction of rs-fMRI signals between two visual conditions. In the visual network, the strength of frequency coupling within 0.03–0.04 Hz was amplified in the EC condition compared with that in the EO condition. By contrast, asking participants to keep their eyes open resulted in the significantly higher cross-frequency interactions between frequency band of 0.02–0.03 and 0.06–0.07 Hz. By using this method, the rs-fMRI signals were decomposed into Hilbert TF maps, allowing spectral localization of the cross-frequency amplitude modulation over time in fMRI signals. By collapsing the temporal information of any pair of TF maps, the ESI map can be used to investigate the frequency coupling between regions, networks, and imaging modalities to thoroughly understand the functional organizations in the brain.


To the Editor—Since the coronavirus disease 2019 (COVID-19) pandemic and associated “shelter in place” orders in the spring of 2020, numerous children in the United States,1 but especially in Michigan,2 have not received the recommended immunizations. Furthermore, baseline Michigan vaccination rates have been low. Here, we describe an effort to address this public health crisis within the COVID-19 crisis.6 was held Saturday, October 10, 2020, in which parents and their children (aged 6 weeks to 18 years) stayed in their vehicles and all participants >2 years old wore required facemasks. The Wayne Pediatrics (WP) clinical group, affiliated with Wayne State University (WSU) School of Medicine (SOM), collaborated with the Detroit Health Department (DHD) to offer the event. Parents were encouraged to call the DHD to schedule a drive-through appointment before the day of the event, but patients who showed up to the event without an appointment were also seen. Before the event, local families were informed about the event through advertising with bulk mailings of postcards, by social media, by e-mail alerts to community partners, and by other widespread marketing publicity.A “drive-through” immunization fair7 were offered to participants due for immunization or requesting influenza vaccine. Immunizations were supplied by the DHD. The WP clinic-building parking lot was used for one-way traffic flow , intake paperwork, and a plastic (sanitizable) clipboard to complete required documentation. Parent identification and insurance cards were verified by DHD staff. The Michigan Care Improvement Registry (MCIR) vaccine record database was accessed for each participant with on-site, mobile computers and printers. The DHD staff reviewed the MCIR record to assess required or past-due immunizations. All participants remained in their vehicle while volunteer clinical staff and medical students picked up the completed forms. Finally, families were guided toward 1 of 2 drive-through lanes and were vaccinated by DHD nurses. The MCIR was updated in real-time, was printed, and was then given to the parent.All volunteer medical and clinical staff with direct patient contact donned the following PPE: mask or respirator, face shield or goggles, gown (when vaccinating a participant), and gloves. Volunteers clearing an initial temperature check and paper-based COVID-19 symptom evaluation form then received ongoing temperature checks every 2 hours. Hand sanitizer was readily available for hand hygiene. All volunteer staff used clinic restrooms that were professionally cleaned after the event.This event took place during the COVID-19 pandemic, with an emphasis on enhanced infection prevention methods for families and volunteers. During the event, 40 participants were successfully immunized.


More severe presentations of diabetic ketoacidosis (DKA) have been reported during the coronavirus disease 2019 (COVID-19) pandemic, possibly due to avoidance of healthcare settings or reduced access to care. To date, no studies have utilized statistical process control to relate temporal COVID-19 events with DKA severity. Our objectives were (1) to determine whether the severity of pediatric DKA presentations changed during COVID-19 and (2) to temporally relate changes in severity with regional pandemic events.This study was a retrospective chart review of 175 patients younger than 18 years with DKA presenting to a pediatric emergency department in the United States between 5/1/2019 and 8/15/2020. As part of our ongoing clinical standard work in ED management of DKA, DKA severity measures, including presenting pH, the proportion of PICU admissions, and admission length of stay, were analyzed using statistical process control.During COVID-19, we found special cause variation with a downward shift in the mean pH on DKA presentation from 7.2 to 7.1 for all patients. The proportion of DKA patients requiring PICU admission increased from 34.2% to 54.6%. Changes temporally corresponded to the statewide bans on large events (3/11/2020), school closures (3/13/2020), and a reduction in our institution’s emergency department volumes. Admission length of stay was unchanged.Pediatric DKA presentations were more severe from March to June 2020, correlating with regional COVID-19 events. Future quality improvement interventions to reduce delayed presentations during COVID-19 surges or other natural disasters should target accessibility of care and public education regarding the importance of timely care for symptoms. This study aimed to explore the association between regional events, public health policies, and associated changes in public attitudes during the COVID-19 pandemic with the severity of DKA presentations in pediatric patients, with the ultimate goal of identifying quality improvement interventions to reduce DKA severity during future COVID-19 surges.Diabetic ketoacidosis (DKA) is a condition sensitive to timely diagnosis, with increased severity noted in those with new-onset diabetes, initial misdiagnosis, and limited access to care.19 The DKA CSW team monitors numerous DKA ED care metrics, allowing for frequent assessments of the quality of ED DKA care and implementing targeted interventions to improve care. This study was conducted as a sub-analysis of the DKA CSW pathway as part of ongoing ED quality and safety efforts.The setting is a free-standing tertiary pediatric referral center located in Seattle, Washington. The hospital ED has 50,000 ED visits annually, with 20% of encounters resulting in admission. This pediatric hospital is the only regional facility providing inpatient pediatric endocrinology services and cares for most pediatric DKA patients in Seattle and the surrounding region. As part of the institution’s model of continuous process improvement, all patients with DKA in the ED are managed on the DKA clinical standard work (CSW) pathway.See figure 1, Supplemental Digital Content 1, which shows the Timeline of COVID-19 events in the Seattle region. A timeline of key events, including the first cases of COVID-19 and pandemic-related public health policies, is noted for the Seattle region. http://links.lww.com/PQ9/A334) The first U.S. case of COVID-19 was confirmed on January 2, 2020, near Seattle, Washington. The Seattle region reported the first U.S. death from COVID-19 on February 29, 2020, at a long-term care facility, which is subsequently associated with an outbreak resulting in 23 deaths.20 Initial social distancing policies were implemented starting 3/11/2020, followed by a stay-at-home policy on 3/23/2020.21 Our institution transitioned to primarily tele-visits for ambulatory subspecialty appointments during the first 2 weeks of March 2020. Many outpatient pediatric practices also transitioned to telemedicine, and reduced in-person well-child visits in late March. Phased community re-opening in the Seattle region started on 6/5/2020.21The Seattle region was among the first locations in the United States impacted by COVID-19. A detailed timeline of events can be seen in Supplemental Digital Content 1.  were included. We included all patients treated for DKA in our ED, including those who presented initially to an outside facility and then transferred to our ED for further care (ED transfers). We planned to exclude patients for whom initial pH at their first hospital presentation was not available; however, no patients met this exclusion criterion.22 Secondary outcomes included other measures of DKA severity, including pediatric intensive care unit (PICU) admission, glucose on presentation (presenting glucose), administration of osmotic fluids  as a proxy for cerebral edema, mechanical ventilation, and inpatient length of stay.This study’s primary objective was to assess the impact of COVID-19 on the severity of pediatric DKA presentations in the ED. The primary outcome measure was pH at the time of presentation to the ED (presenting pH). We used presenting pH at the outside facility before treatment for ED transfers. We selected presenting pH as the primary outcome measure based upon the International Society for Pediatric Diabetes DKA guidelines, which characterize DKA severity based upon presenting pH.23 We chose to utilize SPC as a tool to explore the temporal relationship between specific pandemic events and the severity of DKA presentations. Standard SPC rules were used to define special cause variation.23 SPC charts were annotated with the key events of the COVID-19 pandemic in the Seattle region to correlate them with changes in DKA severity. We used QI Charts 2.0 add-in for Microsoft Excel  to create all SPC charts.We used descriptive statistics to compare the demographics and clinical characteristics of the pre-COVID-19  and COVID-19  groups. We used Mann-Whitney to compare continuous variables and Chi-Square/ANOVA to compare categorical variables. In addition, we used statistical process control (SPC) to analyze the following measures: average presenting pH, average presenting blood glucose level, hospital LOS (days), and PICU admission percentage. SPC charts are useful for monitoring system-level data over time and permit differentiation of normal variation inherent to a process, known as common cause variation, from variation due to an assignable cause, known as special-cause variation.t test and attribute charts (c-charts). Small sample sizes in the subset analysis for patients with new-onset diabetes prevented meaningful SPC analysis for outcomes other than presenting pH. We compared these secondary outcomes, including proportion PICU admission using chi-square test and osmotic fluid administration using Fischer’s exact test. STATA  was used for these analyses.Additional secondary outcomes that were not amenable to meaningful SPC analyses were analyzed using pre- and post-analysis. These included osmotic fluid administration and mechanical ventilation compared between pre-COVID-19 and COVID-19 groups using Fischer’s exact test. Additionally, we compared the mean monthly number of DKA presentations for patients with established and new-onset diabetes using a This study was reviewed and approved by the institution’s Institutional Review Board, which approved waiver of informed consent.P value = 0.02). Patients with new-onset diabetes represented significantly more of the COVID-19 group compared with pre-COVID-19 .Between May 2019 and August 2020, 175 patients were treated in the ED for DKA: 119 pre-COVID-19 and 56 after the onset of COVID-19. All 175 patients met the inclusion criteria. There was an average of 11.9 DKA presentations per month pre-COVID-19 and 10.2 DKA presentations per month in the COVID-19 group. The pre-COVID-19 and COVID-19 groups were similar in age, sex, initial presenting ED location, and preferred language of care ; however, there were insufficient timepoints to meet special cause variation. http://links.lww.com/PQ9/A337.) In contrast, the pattern in the established diabetes c-chart suggests an overall decrease in DKA presentations during the pandemic period. However, there were insufficient timepoints to meet special cause variation criteria.Results of COVID-19 Polymerase Chain reaction (PCR) testing ) were available for 51/56 patients in the COVID-19 group . No changes to the admission criteria were made during the study period. During the baseline period of May 2019 to February 2020, a total of 40 patients with DKA required PICU admission, representing 33.6% of total admissions  Throughout the study period, the average length of stay was 2.0 days. Therefore, the X-bar chart did not meet the criteria for special cause variation. However, in the corresponding S-chart, a decrease in the SD during the weeks of 3/4/2020–3/17/2020 did meet special cause variation.The annotated SPC chart in Supplemental Digital Content 3 shows inpatient length of stay. .The mean number of monthly DKA presentations for new-onset patients and established patients was not significantly different between pre-COVID-19 and COVID-19 groups Table . Althoug18 A survey of pediatric consultants from the United Kingdom reported DKA as the most frequent condition subject to delayed diagnosis in children in the ED/urgent care setting during the COVID-19 pandemic.25 Similarly, in multiple retrospective analyses from Europe and Australia, the COVID-19 pandemic was associated with significant increases in the frequency and severity of DKA presentations in pediatric patients compared with prior years.18This study is the first to confirm increased DKA severity in pediatric patients in the United States during COVID-19 and to utilize SPC analysis to determine the temporal relationship between regional COVID-19 events and the severity of DKA presentations. Our findings are congruent with reports from Europe and Australia, which identified increased frequency and severity of pediatric DKA presentations during the COVID-19 pandemic.4 We hypothesize delayed presentation to care as the primary driver of the increased severity in DKA, consistent with prior studies demonstrating increased DKA severity in those with initially missed diagnosis and limited access to care.12 We theorize public fears of COVID-19 combined with COVID-19-related reductions in access to care were likely responsible for these delays in presentation, ultimately resulting in increased severity of DKA presentations. This possibility may be particularly relevant for those with new-onset diabetes, as there appeared to be a trend of fewer DKA presentations among established diabetics during the pandemic period. Special cause variation in DKA severity persisted through at least early July 2020, followed by a subsequent trend toward the baseline.The timing of special cause variation occurred several weeks following an extensive community outbreak of COVID-19 and during statewide bans on large gatherings (3/11/2020) and school closures (3/13/2020). This period also temporally corresponded to a 72% reduction in our institution’s ED volumes.This study was performed as a sub-analysis of ongoing efforts to monitor and iteratively improve our DKA pathway. Our findings emphasize the potential role of quality improvement (QI) interventions beyond routine care standardization to reduce delayed presentations during future pandemic surges or other natural disasters that limit access to care. Accordingly, we created a key driver diagram to outline potential QI interventions to reduce delayed presentations Fig. .27 Our final key driver, public understanding that it is safe to access healthcare facilities when medically necessary, could be addressed through public health campaigns to bring awareness to the issue of delayed presentation and to emphasize the importance of seeking care when medically necessary.We identified three primary drivers of delayed presentations: (1) access to timely care, (2) caregiver knowledge and recognition of diabetes symptoms, and (3) public understanding that it is safe to access healthcare facilities when medically necessary. Access to timely care could be addressed through expansion and improvements in existing telehealth from both primary care and pediatric endocrinology services. To address the key driver of caregiver knowledge, QI teams should outreach to primary care providers to (1) increase awareness about delayed presentations in children; (2) encourage screening for symptoms of diabetes at every visit and; (3) provide education to families about concerning signs and symptoms of diabetes is needed. For existing patients with diabetes, recent COVID-19 International Society for Pediatric Diabetes guidelines recommend enhanced education of families around sick day management. Specific interventions include (1) review of sick day management with caregiver/patient teach-back at every pediatric endocrinology visit and (2) creating emergency action plans tailored to COVID-19 conditions, including when and where to access emergency care.28 Additionally, prior research has identified racial minorities and those with low socioeconomic status to be at a higher risk of more severe DKA.28 Families with limited computer access and lower health literacy may find access to telemedicine challenging, further reducing disparities in care. Ongoing research to identify potential disparities in COVID-19 associated delayed presentations and access to care for pediatric patients during pandemic surges is needed.The differences noted in racial distribution between the pre-COVID19 and COVID-19 groups may suggest that certain vulnerable populations may be at a higher risk of delayed presentations with DKA. A recent publication from the Centers for Disease Control reported that 4 in 10 adults delayed care due to COVID-19 fears, with increased rates of delayed care in patients with disabilities, chronic illness, and Black and Hispanic adults.29 Our primary outcome, pH on presentation, is also a limitation because this measure could vary depending on the laboratory and method used to calculate pH.Our study has several limitations. First, this was a single-center study in a region of the United States which had the earliest cases of COVID-19. Thus, our findings may not apply to other regions or different periods during the COVID-19 pandemic. Furthermore, unmeasured factors may have contributed to changes in DKA severity. For example, we noted a trend of fewer established diabetes DKA presentations during the pandemic period. This observation could indicate that some patients with established diabetes and mild DKA may have successfully treated their DKA at home and avoided the ED, resulting in a relative skewing of our DKA severity measures.Additionally, increased PICU bed availability during the pandemic may have resulted in more DKA admissions to the PICU, thus increasing the PICU admission rates. Because this was a retrospective chart review, we could not determine if families intentionally delayed care due to fear of healthcare settings or limited access to care resulted in delayed diagnosis. Access to care limitations, including transitions to telemedicine for primary care and endocrinology, and reduced well-child care in the outpatient setting may have further contributed to delayed diagnoses. Finally, although we saw a trend toward baseline in presenting pH and PICU admissions in early July, corresponding to initial re-opening phases in the region, there were insufficient timepoints to meet special cause variation criteria.DKA severity, as assessed by presenting pH, worsened after the start of the COVID-19 pandemic. Similarly, intensive care admission, an indirect proxy for DKA severity, also worsened during the COVID-19 pandemic. There was a temporal association between regional events related to the pandemic and measures of DKA severity. The effects met special cause 2 months after the pandemic’s start as regional social distancing policies came into effect, and they were persistent for at least 3 months. This work emphasizes the need to develop strategies for managing chronic health conditions in pediatric patients during unexpected interruptions in normal care, such as those imposed by the COVID-19 pandemic and other natural disasters. Implementation of QI interventions targeting key drivers of delayed access to care may be a useful first step in this process. Further research is needed to identify particularly vulnerable patients for delayed diagnosis, strategies to prevent delays in care, and the duration of the effects of delayed presentations.The authors have no financial interest in relation to the content of this article.We thank the following team members for their assistance with the study: Anne C. Slater, MD, Assistant Clinical Professor, Seattle Children’s Hospital; James B. Johnson, Clinical Effectiveness Analyst, Seattle Children’s Hospital; and Nathan Deam, Clinical Analytics Manager, Seattle Children’s Hospital.


The novel 2019 coronavirus disease (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2, has spread rapidly around the world and has caused many deaths. COVID-19 involves a systemic hypercoagulable state and arterial/venous thrombosis which induces unfavorable prognosis. Herein, we present a first case in East Asia where an acute superior mesenteric artery (SMA) occlusion associated with COVID-19 pneumonia was successfully treated by surgical intervention.A 70-year-old man presented to his local physician with a 3-day history of cough and diarrhea. A real-time reverse transcriptase-polymerase chain reaction test showed positive for COVID-19, and he was admitted to the source hospital with the diagnosis of moderate COVID-19 pneumonia. Eight days later, acute onset of severe abdominal pain appeared with worsening respiratory condition. Contrast CT showed that bilateral lower lobe/middle lobe and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonia and right renal infarction. In addition, it demonstrated SMA occlusion with intestinal ischemia suggesting extensive necrosis from the jejunum to the transverse colon. The patient underwent an emergency exploratory laparotomy with implementing institutional COVID-19 precaution guideline. Upon exploration, the intestine from jejunum at 100 cm from Treitz ligament to middle of transverse colon appeared necrotic. Necrotic bowel resection was performed with constructing jejunostomy and transverse colon mucous fistula. We performed second surgery to close the jejunostomy and transverse colon mucous fistula with end-to-end anastomosis on postoperative day 22. The postoperative course was uneventful and he moved to another hospital for rehabilitation to improve activities of daily living (ADLs) on postoperative day 45. As of 6 months after the surgery, his ADLs have completely improved and he has returned to social life without any intravenous nutritional supports.Intensive treatment including surgical procedures allowed the patient with SMA occlusion in COVID-19 pneumonia to return to social life with completely independent ADLs. Although treatment for COVID-19 involves many challenges, including securing medical resources and controlling the spread of infection, when severe abdominal pain occurs in patients with COVID-19, physicians should consider SMA occlusion and treat promptly for life-saving from this deadly combination. The novel 2019 coronavirus disease (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly around the world and has caused many deaths . COVID-1Acute mesenteric ischemia, especially superior mesenteric artery (SMA) occlusion, is a critical condition with a high mortality rate of 60–80% which requires urgent diagnosis and treatment . COVID-1A 70-year-old man, who had been taking with aspirin, dabigatran and other medication for atrial fibrillation, hypertension, type 2 diabetes mellitus and dyslipidemia, presented to his local physician with a 3-day history of cough and diarrhea. A real-time reverse transcriptase-polymerase chain reaction test of his nasopharyngeal swab specimen showed positive for SARS-CoV-2 nucleic acid, and he was admitted to the source hospital with the diagnosis of moderate COVID-19 pneumonia. He had been administered one liter of supplemental oxygen via nasal cannula and treated by remdesivir and dexamethasone. Antithrombotic therapy with dabigatran and aspirin for comorbidities was continued after his admission.Eight days later, acute onset of severe abdominal pain appeared, and he was diagnosed as right renal infarction by contrast computed tomography (CT) at that time. Although heparinization was administered immediately, his clinical course was complicated with worsening abdominal pain and respiratory condition. On the next day, he was transferred to our hospital with severe general condition, and intubated immediately. Contrast CT in our hospital showed that bilateral lower lobe/middle lobe and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonia and right renal infarction. In addition, it demonstrated SMA occlusion with intestinal ischemia suggesting extensive necrosis from the jejunum to the transverse colon  on postoperative day 45. As of 6 months after the surgery, his ADLs have completely improved and he has returned to social life without any intravenous nutritional supports for short bowel syndrome.SARS-CoV-2 infection and its disease, COVID-19, have spread rapidly and led the pandemic around the world. COVID-19 has been known a respiratory disease, mainly pneumonia, but also it causes a variety of organ damage . It has This present case is a first report from East Asia about acute SMA occlusion associated with COVID-19 pneumonia. This is presumably because the distribution of COVID-19 epidemics varies among regions in the world, and the situation of the pandemic revealed relatively stable in East Asia, including Japan, compared to other regions. It suggests that if patients with COVID-19 will increase from the current level, it will be necessary to pay attention to this lethal complication even in areas where the pandemic situation has been currently stable.Acute mesenteric arterial occlusion most commonly results from thrombosis based on atherosclerotic disease, or embolism where the embolus originates from the left atrium as a consequence of atrial fibrillation , 24. IntIn our case, due to his medical history of atrial fibrillation, he had been managed with dabigatran since before the thromboembolic complication developed. However, he had multi-site thromboembolism, SMA occlusion and renal infarction. In our literature review, 3 out of 12 patients with a detailed description of their medical history had atrial fibrillation (Table From a viewpoint of infection prevention, in patients with COVID-19, even to perform usual clinical examinations and tests, more human and medical resources are required. This severe medical situation may cause exhaustion of medical staffs and inhibit cooperation between infectious disease specialists and abdominal specialists. In this case, it took about 24 h from the onset of abdominal pain to the diagnosis as SMA occlusion. In case that acute onset of severe abdominal pain occurs in patient with COVID-19, physicians should consider the possibility of SMA thrombosis and examine the patient by contrast CT immediately. Furthermore, it is important to collaborate between infectious disease and abdominal specialists to save their lives from this lethal disease.Necrotic bowel resection is essential for saving lives in most cases of SMA occlusion. In our literature review, 13 cases underwent laparotomy with necrotic bowel resection. It had described the detail of surgical procedures in 9 cased, 4 out of 9 patients were reconstructed with primary anastomosis, and another 5 were constructed intestinal stomas. There were no reports that cases underwent second surgery for intestinal stoma closure. In our case, since the patient's general condition including respiratory function was stable after first surgery, we performed jejuno-transverse colon anastomosis on postoperative day 22. As a result, it was possible to discharge the patient on independent ADLs without intestinal stomas. The decision of whether to perform primary or secondary anastomosis and the optimal timing of secondary anastomosis should be determined, based on the intestinal and general condition, as well as the severity of COVID-19 pneumonia.We have reported a first case of SMA occlusion in a patient with COVID-19 pneumonia in East Asia. Intensive treatment including surgical procedures allowed the patient to return to social life with completely independent ADLs. Although treatment for COVID-19 involves many challenges, including securing medical resources and controlling the spread of infection, when severe abdominal pain occurs in patients with COVID-19, physicians should consider SMA occlusion and treat promptly for life-saving from this deadly combination.


Instrumented gait analysis post-stroke is becoming increasingly more common in research and clinics. Although overall standardized procedures are proposed, an almost infinite number of potential variables for kinematic analysis is generated and there remains a lack of consensus regarding which are the most important for sufficient evaluation. The current aim was to identify a discriminative core set of kinematic variables for gait post-stroke.We applied a three-step process of statistical analysis on commonly used kinematic gait variables comprising the whole body, derived from 3D motion data on 31 persons post-stroke and 41 non-disabled controls. The process of identifying relevant core sets involved: (1) exclusion of variables for which there were no significant group differences; (2) systematic investigation of one, or combinations of either two, three, or four significant variables whereby each core set was evaluated using a leave-one-out cross-validation combined with logistic regression to estimate a misclassification rate (MR).Duration of single-support (MR 0.10) or Duration of 2nd double-support (MR 0.11) phase, corresponding to an 89–90% probability of correctly classifying a person as post-stroke/control. Adding Pelvis sagittal ROM to either of the variables Self-selected gait speed or Stride length, alternatively adding Ankle sagittal ROM to the Duration of single-stance phase, increased the probability of correctly classifying individuals to 93–94% (MR 0.06). Combining three variables decreased the MR further to 0.04, suggesting a probability of 96% for correct classification. These core sets contained: (1) a spatial (Stride/Step length) or a temporal variable (Self-selected gait speed/Stance time/Swing time or Duration of 2nd double-support), (2) Pelvis sagittal ROM or Ankle plantarflexion during push-off, and (3) Arm Posture Score or Cadence or a knee/shoulder joint angle variable. Adding a fourth variable did not further improve the MR.The best MR for one single variable was shown for the A core set combining a few crucial kinematic variables may sufficiently evaluate post-stroke gait and should receive more attention in rehabilitation. Our results may contribute toward a consensus on gait evaluation post-stroke, which could substantially facilitate future diagnosis and monitoring of rehabilitation progress. Instrumented motion analysis is increasingly used to evaluate movement patterns during gait post-stroke . It servThe focus of gait analysis is commonly on the lower limbs. Recent studies nevertheless emphasize the importance of incorporating also the trunk and upper limbs, particularly in post-stroke gait analyses, since this information adds to the understanding of balance control, energy expenditure and functional ability . In addiThis cross-sectional study involved 31 persons post-stroke and 41 non-disabled controls. Characteristics of the participants are presented in ®, Qualisys Gothenburg, Sweden). Data were recorded from the middle 3 m of the walkway and included 2–4 gait cycles for each trial. The data were analyzed using the Qualisys Track Manager software , filtered  and processed in Visual 3D .Gait analyses were performed in the U-Motion Laboratory at Umeå University, Sweden. Seventy-two reflective markers were attached to anatomical locations according to a full-body model described in detail previously . MarkersIncluded kinematic variables are presented in The statistical approach consisting of three steps, briefly presented below, followed the main setup in In order to identify one or several potential core sets of variables, we systematically investigated all combinations consisting of 1–4 variables obtained from the complete set of all those variables that were significantly different between groups. Each core set was evaluated using leave-one-out cross-validation in combination with logistic regression to estimate the different models’ misclassification rate (MR) (Step II). For each core set, a logistic regression model based on the variables in the core set, with no interaction terms, was used to model the probability that the person (that was left out) belonged to the group of persons post-stroke. The default threshold of 0.5 was used for classification, implying that for an estimated probability above 0.5, the person was classified as post-stroke. The MR was estimated as the proportion of wrongly classified individuals. Confusion matrices that identified the rates of true positive, true negative, false positive, and false negative classifications were also considered. To add information about potential relationships between the variables, Spearman’s rank correlation was used to estimate the pair-wise correlations between the variables of interest. All analyses were performed in R .The first step in the analysis process identified which variables that were significantly different between persons post-stroke and non-disabled controls see .Duration of single-support phase in the affected side (Duration of 2nd double-support phase classified 89% (MR 0.11), and Stride length 87% (MR 0.13) of the persons correctly. A core set of two variables resulted in MRs ranging from 0.06 to 0.42. The lowest rate (MR 0.06) was shown for Step length/Stride length in combination with Pelvis sagittal ROM (pelvis anterior/posterior tilt). These two combinations of variables classified 94% of persons correctly. Combining three variables decreased the MR further to 0.04 (range: 0.04–0.42). Each core set of three variables correctly classified 96% of persons. A spatial (Stride length/Step length) or temporal variable (Self-selected gait speed/Stance time/Swing time/Duration of 2nd double-support) was combined with either Pelvis sagittal ROM or Ankle plantarflexion, terminal stance (during push-off). In addition, these variables were combined with either Arm Posture Score, Cadence, or a knee or shoulder joint angle variable, to generate the best possible MR based on our populations. Adding yet another variable did not decrease the MR further, nor did it change the types of variables included in the core sets . The combination of exclusively spatial and temporal gait variables  that most correctly classified persons post-stroke was Stride width, Cadence, Duration of stance phase and Duration of 2nd double-support phase  was shown for the ted side . This cort phase . This coSince the MR does not include information about whether the different models are better at classifying post-stroke persons or controls, this was addressed with confusion matrices to identify the rates for true positive (0.39), true negative (0.57), false positive (0.00), and false negative (0.04) classifications. These values are valid for all core sets of size three with MR equal to 0.04. The results showed that persons post-stroke and controls were classified correctly to a similar extent in the models with low MRs.When investigating potential relationships between the variables, correlation analyses were performed based on pooled data from both groups but also calculated separately for each group . The corDuration of single-support (MR 0.10) followed by the Duration of 2nd double-support (MR 0.11). Adding Pelvis sagittal ROM to the specific temporal or spatial variables  . The mosbles see  generateDuration of single- or 2nd double-stance (longer in persons post-stroke), Self-selected gait speed and Stride/Step length , are common, well-established variables used for evaluation of gait in persons post-stroke .Several of the gait variables represented in the core sets, such as the t-stroke . As conft-stroke  and in at-stroke , these vPelvis sagittal ROM or knee/shoulder kinematics. When used independently, several variables had a higher probability of correctly differentiating persons post-stroke from controls than Pelvis sagittal ROM. But when Pelvis sagittal ROM was used in combination with other variables, it generated improved MRs and thus seems highly relevant for post-stroke gait analysis. Indeed, two-thirds of the here presented core sets combining 2–3 variables included this specific variable. The pelvis connects the trunk to the lower limbs, and muscular control at the pelvis has been suggested to be crucial for dynamic balance and weight transmission during walking  are of particular importance when classifying gait post-stroke. These two variables were represented in several emerging core sets. For the Knee sagittal ROM, estimates of the minimal detectable change and the minimal clinically important difference have been established for persons post-stroke  were represented in several suggested core sets of variables, providing further evidence that the upper limbs influence post-stroke gait movement pattern. An increased shoulder abduction angle among persons post-stroke (Shoulder abduction MAX) seems characteristic for post-stroke gait and has been assumed to be part of a compensatory strategy to help improve body weight distribution and balance  in the present study with another temporal variable, such as Duration of swing or Temporal asymmetry, the MR improved to 0.09. The combination of spatial and temporal variables that most correctly seems to classify persons post-stroke and controls included Stride width, Cadence, Duration of stance and Duration of 2nd double-support. Together these four variables classified persons correctly with a 93% probability.The potential for assessing the core set variables in a clinical context differs. The spatial and temporal variables are most accessible in clinics today since this data can be gathered relatively efficiently with the use of, e.g., pressure-sensitive walkways or timing devices. Self-selected gait speed is one of the most commonly used outcome measures. By combining Arm Posture Score is currently based on comprehensive 3D upper limb joint position data, whereas estimating the Sagittal ROM Shoulder Index requires bilateral shoulder flexion/extension data. Low-cost webcam technology has, however, shown potential for real-time tracking of joint kinematics, particularly in the sagittal plane and if performed following specific recommendations related to data collection setup and camera and analysis software .The purpose of Step II of the current analytical approach was to identify potential core sets of variables for discussion and future research toward a consensus on crucial variables for the kinematic evaluation of gait post-stroke. The focus of the current paper was not on checking model assumptions, interpreting parameter estimates, or comparing models in other ways than their classification ability. If identified core sets are to be used further in similar analyses, these assumptions should be checked. One specific assumption relates to the lack of multicollinearity, i.e., that the variables included in the model are not highly correlated. Note that gait speed and cadence were identified in the same core set and that these variables seem significantly correlated both in our analyses . The patients/participants provided their written informed consent to participate in this study.HN, DL, CH, and GJ formulated the research question. CH and LS obtained the funding. HN and GJ performed the data collection and data preparations. LS performed the quantitative data analysis. HN drafted the preliminary manuscript. All authors helped in further writing and critical reviewing of the manuscript, read, and approved the final manuscript.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Betacoronavirus that has caused nearly 200 million cases and the COVID-19 pandemic has resulted nearly 5 million deaths world wide [SARS-CoV-2 is a novel Lung damage has been suggested as the main cause of morbidity and mortality in COVID-19. The extent of lung involvement in patients with COVID-19 could range from asymptomatic to overt adult respiratory distress syndrome requiring intubation. Our current understanding of the biological basis for the disease course and complications in COVID-19 is rapidly evolving. Further advances in our understanding of pathophysiology of COVID-19 will also enable us to have a closer look into the routinely used medications, such as anticoagulants, in the routine care of these patients. Many pharmaceutical companies already published several randomized controlled trials (RCTs) and started new ones with novel investigational therapeutics. Global recommendation and RCTs are important for effective therapeutic options and strategies, particularly for moderate to severe cases. This editorial reviews the current knowledge about thrombosis, fibrosis and efficacy of anticoagulation regimens in preventing these two mutually inclusive biological processes in COVID-19. The editorial reviews the pathophysiology of COVID-19 to explain the differences in findings between RCTs and potential novel targets for future studies.d-dimer levels in the circulation. Elevated d-dimer levels are a biomarker of poor prognosis in COVID-19 [The autopsy and pathological studies in the lungs of COVID-19 patients report that there are widespread capillary fibrinous microthrombi and fibrin at the microvascular level . FibrinoCOVID-19 .The causes of thrombosis in COVID-19 patients have been investigated extensively over the last couple years. Inflammation has been suggested as the cause of thrombosis in COVID-19. Studies report that intense and widespread inflammation exists in vascular system of COVID-19 patients . There iThe other potential cause for thrombosis is the dysfunction of protective proteins in the setting of severe inflammation as a result of COVID-19. Pathophysiology of COVID-19 involves the attachment to the spike protein of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor . A recenBinding of virus to ACE2 downregulates ACE2. ACE2 is protective and ACE2 also counterbalances the deleterious effects of angiotensin II (Ang II) by converting Ang II to angiotensin 1–7. Loss of ACE2 forms a biochemical pathway that is central in COVID-19 pathophysiology. Loss of ACE2 activates the renin–angiotensin–aldosterone system (RAAS) and exacerbates the harmful effects of Ang II such as thrombosis, tissue proliferation and fibrosis. Activated RAAS is a well-known cardiovascular risk factor in atherosclerosis, kidney and heart failure . Yet, inAdministration of proven therapies to patients who are in urgent need and effective utilization of healthcare resources are current and global challenges. Over the last 2 years, our understanding of the pathophysiology of COVID-19 has progressed. We now understand the roles of several biological systems ranging from inflammation, vascular biology, RAAS, hemostasis, coagulation and fibrosis in COVID-19. Yet, there is presently no uniformly and globally accepted treatment algorithms for COVID-19. Protocols widely vary between hospitals and countries . Treatment modalities include supportive measures with oxygen therapy, antivirals, antibiotics for secondary infections, steroids, anticoagulants and immune modulators. Intubated patients who are refractory to treatment often require tocilizumab, and other novel immunomodulatory therapies. There remains an urgent need to develop targeted and proven therapies in COVID-19. A fundamental understanding of the pathophysiology of COVID-19 is required to elucidate the role of current management strategies and therapeutic interventions.Coagulation disturbances observed in COVID-19, and the potential risk of embolism, have prompted several studies evaluating anticoagulants as a treatment strategy to reduce mortality and morbidity. This is followed by rapidly designed RCTs in patients with confirmed COVID-19 with subsequent plan to develop global recommendations.Observations report the incidence of pulmonary embolism is increased in critically ill COVID-19 patients . Expert The Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) and Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC) are the three large, multicenter RCTs in patients with confirmed COVID-19 infection. These three large platforms examine anticoagulation treatment protocols with subsequent aim to develop global recommendations . The thrWe should look into the reasons for the trial results in view of the complex pathophysiology of COVID-19. Initial observations of increased of pulmonary embolism in COVID-19, as demonstrated by clinical, imaging and laboratory evidence have changed our perceptions of COVID-19. Full-dose anticoagulation regimens in these patients with frequent and multiple comorbidities naturally impose an inherent bleeding risk. Trial results indicate that anticoagulation confers an increased bleeding risk in aggressive protocols for COVID-19 patients.As a result, the above mentioned RCTs suggest that ‘routine and full-dose anticoagulation’ in the ICU in critically ill COVID-19 patients is not beneficial and in fact can be harmful in some patients . The finIn this context, we should pay special attention to the observations which indicate that hospitalized patients with COVID-19 display wide physiological and biological heterogeneity . Even thd-dimer levels are associated with poor prognosis in COVID-19 [Given the higher prevalence of the disease in patients with multiple comorbidities, many of the COVID-19 patients are on antiplatelet drugs, and/or anticoagulation for underlying vascular pathologies at baseline. Therefore, RCT results suggest that therapeutic strategies in COVID-19 such as anticoagulation should prompt caution for close monitoring. This is particularly important to avoid complications, since the fibrinolytic system is also dysregulated in critically ill patients with COVID-19 . The plaCOVID-19 .Fibrinolytic system is involved in a wide range of biological processes like atherosclerosis, thrombosis, fibrosis, cancer, inflammation, aging, apoptosis and infection . The rolPrior study reveals that increase in both PAI-1 and t-PA levels are common in critically ill COVID-19 patients . SimilarSeveral other reasons exist for dysregulation of fibrinolysis and its components in COVID-19. Unopposed effects of Ang II in COVID-19 result in increased expression of PAI-1 in endothelial cells . Ang II Experimental and clinical studies in COVID-19 indicate that interaction between the RAAS and the coagulation system plays a role in the pathophysiology of COVID-19 ,14,15. RThe target organs that are commonly affected are the pulmonary and the cardiovascular systems, leading to respiratory failure, heart failure and coagulopathy in critically ill patients. Cytokine storm in during the viral infection can dysregulate defense mechanisms such as ACE2 and endogenous fibrinolysis. Patients experience rapid development of acute inflammatory pulmonary edema as a result of the elevated levels of Ang II, thromboembolism and fibrosis . AnticoaAs a result RAAS is activated and fibrinoltic system is inhibited. Both of which set the stage for the thrombotic tendency and fibrosis in COVID-19 ,14–16. DThe role of PAI-1 in COVID-19 has not yet been extensively studied, but building data indicate that this hypothesis merits further attention [Antithrombotic therapy in critically ill patients is often utilized with the common goal of prevention of embolism. Coagulation factors are serine proteases of the coagulation cascade composed of the intrinsic and extrinsic pathways, leading to the formation of thrombin. Increasing evidence suggests that thrombin exerts nonhemostatic cellular effects that are involved in pathophysiological conditions, such as atherosclerosis, inflammation and fibrosis. For example, anticoagulation with enoxaparin, a low molecular-weight heparin, not only prevents development of venous thrombosis in debilitated patients, but also improves survival . AnticoaImpaired fibrinolysis and hypercoagulable state contribute to microthrombi and fibrin deposition as the pathogenesis of acute and subacute lung injury in COVID-19. To overcome activated RAAS, and depressed fibrinolysis, fibrinolytic agents and PAI-1 inhibitors are potential new horizons in the management of COVID-19 lung injury.Several studies utilize tPA, uPA, plasminogen, plasmin and PAI-1 inhibitors. In animal models and experimental studies, activation of fibrinolytic system can reverse lung injury and increase oxygenation with reduction in mortality. Several ongoing trials assess these therapies by investigational new drugs for decreasing lung injury in the setting of COVID-19.ACE2–SARS-CoV-2 attachment modifies ACE2 catalytic activity, and alters the bradykinin, RAAS and coagulation systems . StudiesFor instance, flavonoids including quercetin are water-soluble plant pigments with antioxidant capacity, abundant in fruits and plants . StudiesSimilarly, Toll-like receptors (TLRs) are involved in the defense against viral infection and its complications of COVID-19 . RCTs arUnder these unprecedented challenges and circumstances, multiple trials for potential drugs and vaccines are ongoing. Similarly, effective vaccines, vaccine equity, planetary health measures to ensure the quality of care globally are ongoing discussions.The discovery of novel therapeutics against the novel coronavirus can contribute to the global efforts for therapeutics innovation for the COVID-19 care pandemic by anticoagulation, anti-inflammatory and antifibrotic remedies. Omics systems science approaches in the future and harnessing the local and global medicine can help us to develop personalized strategies in COVID-19. As is the case for anticoagulation in COVID-19, the results of ongoing trials will verify the benefit of novel therapeutics and strategies in the care of patients with COVID-19.Understanding the balance between coagulation, fibrinolysis and hemostasis will help the clinician to develop optimal approaches to thrombosis prophylaxis in COVID-19. Growing data indicate that thrombosis, fibrinolysis and homeostasis in COVID-19 are complex with subsets of patients that display a tendency for bleeding rather than thrombosis. For instance, recent study indicates that a hyperfibrinolytic state can exist in some COVID-19 patients with poor outcome . Therefo


Was a hotel-based protective housing intervention associated with reduced incidence of SARS-CoV-2 infection among persons experiencing homelessness (PEH) in Chicago, Illinois?In this cohort study of 259 PEH, a significant reduction in SARS-CoV-2 incidence was observed during the study period among PEH provided with protective housing compared with PEH in shelters citywide. Improvements in hypertension and glycemic control were also observed; 51% were successfully housed at departure.These findings suggest that protective housing interventions may reduce SARS-CoV-2 incidence among PEH at increased risk for severe COVID-19. This cohort study examines the association of a hotel-based protective housing intervention and the incidence of SARS-CoV-2 infection among persons experiencing homelessness in Chicago, Illinois. Persons experiencing homelessness (PEH) are at higher risk for SARS-CoV-2 infection and severe illness due to COVID-19 because of a limited ability to physically distance and a higher burden of underlying health conditions.To describe and assess a hotel-based protective housing intervention to reduce incidence of SARS-CoV-2 infection among PEH in Chicago, Illinois, with increased risk of severe illness due to COVID-19.This retrospective cohort study analyzed PEH who were provided protective housing in individual hotel rooms in downtown Chicago during the COVID-19 pandemic from April 2 through September 3, 2020. Participants were PEH at increased risk for severe COVID-19, defined as (1) aged at least 60 years regardless of health conditions, (2) aged at least 55 years with any underlying health condition posing increased risk, or (3) aged less than 55 years with any underlying health condition posing substantially increased risk .Participants were housed in individual hotel rooms to reduce the risk of SARS-CoV-2 infection; on-site health care workers provided daily symptom monitoring, regular SARS-CoV-2 testing, and care for chronic health conditions. Additional on-site services included treatment of mental health and substance use disorders and social services.1c, and housing placements at departure.The main outcome measured was SARS-CoV-2 incidence, with SARS-Cov2 infection defined as a positive upper respiratory specimen using any polymerase chain reaction diagnostic assay authorized for emergency use by the Food and Drug Administration. Secondary outcomes were blood pressure control, glycemic control as measured by hemoglobin AP = .001). There was also an adjusted change in systolic blood pressure at a rate of −5.7 mm Hg  and hemoglobin A1c at a rate of −1.4%  compared with baseline. More than half of participants (51% [n = 132]) departed from the intervention to housing of some kind .Of 259 participants from 16 homeless shelters in Chicago, 104 (40.2%) were aged at least 65 years, 190 (73.4%) were male, 185 (71.4%) were non-Hispanic Black, and 49 (18.9%) were non-Hispanic White. There was an observed reduction in SARS-CoV-2 incidence during the study period among the protective housing cohort  compared with citywide rates for PEH residing in shelters , such housing interventions may reduce the risk of SARS-CoV-2 infection, improve noncommunicable disease control, and provide a pathway to permanent housing. Difficulty maintaining physical distance, as well as challenges in obtaining personal protective equipment, can make SARS-CoV-2 transmission more likely among PEH.Persons experiencing homelessness (PEH) are at increased risk of becoming infected with SARS-CoV-2 and developing COVID-19. Studies across the US and Europe have identified a high incidence of SARS-CoV-2 in PEH, particularly among those in congregate settings.5 with multiple studies documenting poor rates of blood pressure control.8 Although prevalence of diabetes in PEH may be comparable with other low-income populations,5 the likelihood of adequate glucose control is substantially lower9 resulting in higher complication rates.10Importantly, PEH also have a higher prevalence of underlying health conditions that place them at higher risk for severe illness or death from COVID-19. The prevalence of hypertension is estimated to be 50% among PEH in the US,11 or isolation and quarantine measures for PEH who tested positive.12 This Chicago model, in contrast, provided protective housing for PEH who were at risk for severe illness and death from COVID-19 owing to older age or underlying health conditions. We are not aware of any published assessments of similar protective housing efforts. In addition to individualized hotel rooms, on-site health care workers provided symptom monitoring, regular SARS-CoV-2 testing, and medical care for chronic health conditions. Other key services included meal delivery, treatment of mental health and substance use disorders (SUDs), as well as social services. Although hotel conversions to expand supportive housing existed before the pandemic, the COVID-19 pandemic provided an accelerated opportunity to pilot a model targeted to PEH with high-risk health conditions.In April 2020, a hotel-based protective housing intervention was implemented in Chicago, Illinois, through a joint effort by the Chicago Departments of Public Health (CDPH), Family and Support Services (DFSS), and Housing (DOH), in conjunction with Lawndale Christian Health Center (LCHC), a federally qualified health center with longstanding experience in providing health care to PEH. Published assessments of interventions elsewhere have focused on widespread testing to interrupt transmission of COVID-19 in congregate settings,The primary aim of this study was to describe Chicago’s hotel-based protective housing intervention and assess whether the intervention was associated with any differences in the incidence of SARS-CoV-2 infection among those participating in the intervention relative to the citywide population of sheltered PEH. Secondary aims were to assess change in high-risk health conditions during the study period, including hypertension and diabetes; describe treatment for mental health conditions and SUDs; and describe housing outcomes on departure from the intervention.13 has been described elsewhere.11 Just prior to the pandemic, there were an estimated 5390 persons experiencing homelessness in Chicago.14 Few (10.2%) were aged at least 60 years; the majority were male (61.6%) and non-Hispanic Black (77.0%); most resided in homeless shelters (72.2%). Available data indicated high prevalence of cardiovascular and respiratory conditions, diabetes, tobacco use, physical disabilities, mental health conditions and SUDs,14 many of which are known to increase risk of severe illness from COVID-19.15We conducted a retrospective cohort study of PEH who consented to participate in a hotel-based housing intervention between April 2 and September 3, 2020. All participants were offered temporary housing in individual hotel rooms leased by the City of Chicago. Chicago’s overall response to the COVID-19 crisis among PEH, implemented with support from the Chicago Homelessness and Health Response Group for Equity (CHHRGE),2 it became clear that isolation of symptomatic individuals was likely insufficient to interrupt transmission of SARS-CoV-2 in homeless shelters. On April 10, the hotel was repurposed as protective housing for PEH who were at increased risk of severe illness from COVID-19 and not suspected to have SARS-CoV-2 infection.On April 2, 2020, the City of Chicago established an isolation facility for PEH in downtown Chicago. The facility, which opened at a time when SARS-CoV-2 testing was not widely available, was initially intended for housing people with possible COVID-19 infection while test results were pending. However, with growing evidence of asymptomatic transmission and high infection rates in shelters across Chicago and other large metropolitan areas,STROBE) reporting guideline for cohort studies. The study intervention received a nonresearch determination as part of a public health emergency response; retrospective assessment of the intervention was approved with a waiver of informed consent from the University of Chicago institutional review board.The reporting of this study follows the Strengthening the Reporting of Observational Studies in Epidemiology (16 or (3) aged less than 55 years with any underlying health condition posing substantially increased risk . Underlying health conditions included hypertension, diabetes (type 1 or 2), obesity, immune compromise, and chronic respiratory conditions.16 Substantially increased risk was assessed on a case-by-case basis, through discussions between team physicians and medical epidemiologists.Eligibility for protective housing included any PEH, whether residing in a shelter, in an encampment, or on the street, who met criteria for being at increased risk for severe illness due to COVID-19, defined as (1) aged at least 60 years regardless of health conditions, (2) aged at least 55 years with any underlying health condition posing increased risk,To identify eligible PEH, CDPH/DFSS requested that congregate shelters with at least 10 people sharing a dormitory generate a provisional list of eligible residents. An experienced physician visited each shelter to confirm eligibility, identify other potentially eligible residents, and conduct in-person risk assessments for mobility accommodations, medications, and possible withdrawal from substances. Individuals gave oral consent for participation. Race and ethnicity and other sociodemographic information were self-reported.Protective housing included a private hotel room with a bathroom and shower, Wi-Fi, TV, and meal delivery; security and laundry services were subcontracted. Medical services included universal SARS-CoV-2 polymerase chain reaction (PCR) testing on or soon after admission; daily assessments for signs and symptoms of COVID-19; access to regular medications, including treatments for opioid, alcohol, and tobacco use disorders ; primary care and behavioral medicine visits; wound and foot care; access to specialist services such as on-site podiatry; and referral to an acute care facility as necessary. COVID-19 assessments included temperature checks, oxygen saturation checks, and a symptom questionnaire. Medical staff provided 24-hour coverage and included up to 9 full-time providers  who typically provided care in LCHC outpatient clinics. Daily pharmacy deliveries facilitated rapid medical treatment. Social services included case management and assistance with housing.To minimize the risk of SARS-CoV-2 spread, movement into and out of the hotel was initially restricted. During the first month of operations, when details about the transmissibility of SARS-CoV-2 infection were still emerging, participants were largely confined to their own rooms. After the first month, adjustments were made so that guests could leave to complete necessary tasks . Smoke breaks and other socially distanced activities were instituted, such as supervised exercise breaks on the hotel rooftop, magic shows by one of the guests, walks around the block, and other activities.The primary outcome of interest was the incidence of SARS-CoV-2 infection. SARS-CoV-2 infection was defined as any individual with a positive upper respiratory specimen using any PCR diagnostic assay authorized for emergency use by the Food and Drug Administration. Individuals were included in the protective housing cohort if they were admitted on or after April 10, when protective housing began, or if they converted from the isolation to protective housing cohort after negative SARS-CoV-2 testing. Incidence among the protective housing cohort was compared to incidence among PEH residing in shelters citywide. A detailed summary of the methodology for estimating SARS-CoV-2 infection among sheltered PEH in Chicago is included in the eMethods in the 1c) measurements were extracted from the Electronic Health Record and analyzed as continuous variables. Additional outcomes related to mental health, SUD, and housing were also recorded and summarized.Secondary outcomes included the status of known modifiable risk factors for severe illness due to COVID-19, including hypertension and diabetes control. Repeated systolic blood pressure (SBP), diastolic blood pressure (DBP) and hemoglobin A1c (HbAP < .05) between the incidence of SARS-CoV-2 infection among those receiving protective housing and those residing in shelters citywide.Sociodemographic and shelter characteristics of the sample were described. Incidence among the protective housing cohort was calculated as the number of participants who were provided with protective housing and tested positive for SARS-CoV-2 divided by the total number of participants who were provided with protective housing. Incidence among sheltered PEH citywide was calculated as the number of reported SARS-CoV-2 infections divided by the number of susceptible sheltered PEH in Chicago who were not part of the protective housing intervention (see eMethods in the 1c measurements as a function of intervention time (baseline vs pooled follow-up measurements). The same model was applied for all outcome measures, grouping observations by patient identifier and implementing robust standard errors. Each model adjusted for all theoretically relevant confounders, including sociodemographic characteristics , comorbid mental health conditions and/or SUDs, shelter of origin, day at the hotel , and total days at the hotel. The day at the hotel was modeled as a time-varying covariate; all other covariates were time invariant. While GEE is a common statistical approach used in public health , we also conducted sensitivity analyses using traditional fixed effects models to assess for within subject change over time.In secondary analyses of chronic illness, we used generalized estimating equations (GEE) in population-averaged longitudinal regression models to independently assess blood pressure and HbAOf 259 PEH admitted to the hotel from 16 homeless shelters . Monthly analysis found a large difference between cohorts in April 2020, when the bulk of outbreaks were occurring in congregate shelters, followed by a decline in incidence to low levels across both cohorts  were obtained within 5 days of admission to the hotel. The overall incidence of COVID-19 among protective housing participants was 54.7 per 1000 people  compared with 137.1 per 1000  among PEH residing in shelters citywide  were transferred to a hospital for severe illness due to COVID-19  had a self-reported underlying diagnosis of diabetes, of which 23 had a measured HbA1c greater than 7%.18 In models examining change in chronic illness measurements during the intervention period relative to baseline . We observed no significant changes in DBP during the intervention period. In sensitivity analyses using fixed effects models, changes were substantively similar , 141 (54.4%) had a self-reported underlying diagnosis of hypertension, of which 84 had a measured SBP greater than or equal to 130 mm Hg or DBP greater than or equal to 80 mm Hgbaseline , we obseAmong all 259 study participants, 146 (56.4%) had mental health conditions (eTable 3 in the Eighty-nine participants (34.4%) had SUD, and 52 (20.1%) had both mental health and SUD diagnoses. Of those with SUD, 24 were supplied daily methadone or sublingual buprenorphine-naloxone, and 9 were newly initiated on buprenorphine-naloxone. Nearly half of participants  used tobacco, of which 80 received medication to reduce or stop tobacco use.Approximately half of all study participants  departed the hotel to some form of permanent, transitional, or other housing . Of the In this Chicago-based cohort study of persons experiencing homelessness who were at increased risk of severe illness from COVID-19, we found that a rapid-entry hotel-based protective housing intervention was associated with a 2.5-fold reduction in the incidence of SARS-CoV-2 infection compared with citywide rates among sheltered PEH. These findings suggest that targeting high-risk individuals for protective supportive housing can be an effective strategy to minimize morbidity and mortality due to COVID-19. Protective housing, in addition to quarantine and isolation facilities, will be key to building resiliency against the potential for ongoing surges of COVID-19, as well as other local disease outbreaks.19 We observed similarly moderate reductions in HbA1c compared with meta-analyses of lifestyle change19 and drug therapy.20 In addition, 28.1% of participants with a mental health condition were newly initiated on psychiatric medications; and 10.1% of participants with SUD were newly initiated on treatment for opiate use disorder. We speculate that temporary stabilization housing for PEH with complex medical, behavioral, and social needs may be an important means of interrupting cyclical utilization of emergency department and hospital services, as well as cycling through jails, prisons, and other settings.21Beyond emergency preparedness, our study has several implications for policies regarding the intersecting health and social needs of PEH. First, in addition to improvements in COVID-19 outcomes, we documented improvements in disease control, as well as support for participants’ mental health and SUD. We observed a reduction in SBP of 5.7 mm Hg, consistent with a moderate effect in intervention-based studies.Second, the intervention addressed gaps in Chicago’s shelter to housing continuum. The pandemic presented a unique opportunity for multisector coordination between city agencies, shelters, primary care clinics, behavioral health and SUD specialists, and housing organizations, resulting in more streamlined case management and housing placements. From a policy standpoint, COVID-19–related infusion of emergency response funding and resources may provide city public health departments with an unprecedented opportunity to explore noncongregate shelter options with varying levels of medical supports that will better serve residents in need of temporary housing. The City of Chicago, for example, broadly recognized the importance of transforming the physical footprint of its emergency housing system to reduce reliance on large congregate facilities, particularly for individuals at high risk of adverse outcomes in those settings. Importantly, flexible, integrated, and sustained funding sources at the federal, state, and local levels are needed to enable acquisition, renovation, and capital improvement of new and existing shelter facilities. Support is also needed to fund initiatives that proactively identify PEH with high-risk medical and behavioral health needs, and provide intensive, whole-person services to stabilize their conditions and facilitate a successful transition to permanent supportive housing.This study has several limitations. First, measurement of SARS-CoV-2 infections among citywide PEH was based on reporting to CDPH. Although enhanced reporting , it is possible that observed reductions may be due to regression to the mean.Third, this is a single-site study of a novel protective housing model for PEH in Chicago and may not be widely generalizable. However, this intervention is likely replicable in other dense, urban areas where congregate settings are a predominant form of housing for PEH. Fourth, social distancing and infection control measures made medical interventions more challenging, which potentially limited improvements in the management of chronic conditions. Fifth, because a comparison group was not available for secondary measures (BP and HbAFinally, in response to George Floyd’s murder and resulting demonstrations that occurred directly outside the hotel, the intervention team eased restrictions for movement to and from the hotel, thereby increasing participant autonomy. Although this increased movement may have impacted the outcome of the protective housing intervention, these steps were necessary to recognize and address the role of systemic racism in perpetuating health and housing inequities among PEH.This cohort study found that a hotel-based protective housing intervention was associated with marked reduction in the incidence of SARS-CoV-2 infection among study participants. A large proportion of PEH who received integrated medical and social services also appeared to achieve improvements in their chronic health conditions, received treatment for mental health conditions and SUDs, and departed the intervention to permanent housing. This model is not only relevant for the pandemic era, but is a critical piece to addressing the heterogeneous needs of PEH across the US.