Enterobacteriaceae that produce extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases (ACBLs) are important pathogens and can cause community-acquired illnesses, such as urinary tract infections (UTIs). Fecal carriage of these resistant bacteria by companion animals may pose a risk for transmission to humans. Our work evaluated the sharing of ESBL- and ACBL-producing E. coli isolates between humans and companion animals. We found that in some households, dogs carried the same strain of ESBL-producing E. coli as the household member with a UTI. This suggests that transmission events between humans and animals (or vice versa) are likely occurring within the home environment and, therefore, the community as a whole. This is significant from a health perspective, when considering measures to minimize community transmission, and highlights that in order to manage community spread, we need to consider interventions at the household level. Escherichia coli bacteria are the most common cause of community-acquired multidrug-resistant urinary tract infections (UTIs) in New Zealand. The carriage of antimicrobial-resistant bacteria has been found in both people and pets from the same household; thus, the home environment may be a place where antimicrobial-resistant bacteria are shared between humans and pets. In this study, we sought to determine whether members (pets and people) of the households of human index cases with a UTI caused by an ESBL- or ACBL-producing E. coli strain also carried an ESBL- or ACBL-producing Enterobacteriaceae strain and, if so, whether it was a clonal match to the index case clinical strain. Index cases with a community-acquired UTI were recruited based on antimicrobial susceptibility testing of urine isolates. Fecal samples were collected from 18 non-index case people and 36 pets across 27 households. Eleven of the 27 households screened had non-index case household members  positive for ESBL- and/or ACBL-producing E. coli strains. Whole-genome sequence analysis of 125 E. coli isolates  from these 11 households showed that within seven households, the same strain of ESBL-/ACBL-producing E. coli was cultured from both the index case and another person (5/11 households) or pet dog (2/11 households). These results suggest that transmission within the household may contribute to the community spread of ESBL- or ACBL-producing E. coli.Extended-spectrum-beta-lactamase (ESBL)- or AmpC beta-lactamase (ACBL)-producing IMPORTANCEEnterobacteriaceae that produce extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases (ACBLs) are important pathogens and can cause community-acquired illnesses, such as urinary tract infections (UTIs). Fecal carriage of these resistant bacteria by companion animals may pose a risk for transmission to humans. Our work evaluated the sharing of ESBL- and ACBL-producing E. coli isolates between humans and companion animals. We found that in some households, dogs carried the same strain of ESBL-producing E. coli as the household member with a UTI. This suggests that transmission events between humans and animals (or vice versa) are likely occurring within the home environment and, therefore, the community as a whole. This is significant from a health perspective, when considering measures to minimize community transmission, and highlights that in order to manage community spread, we need to consider interventions at the household level. Escherichia coli is a commensal microorganism found both inside and outside the mammalian large intestine and is commonly used as an indicator of fecal contamination  urinary tract infections (UTIs) (E. coli (mination . E. colis (UTIs) . Treatmes (UTIs) , particus (UTIs) . Increas UTIs in the New Zealand community  that are usually associated with human extraintestinal infection (Staphylococcus aureus was observed in 57% of positive humans and pets sharing the same household environment (Staphylococcus species in other studies (S. aureus (MRSA) transfer events  within households has also been observed .This study aimed to evaluate whether the same strains of ESBL- or ACBL-producing Seventy-two human index cases  were invited to submit fecal samples from themselves, as well as any other members of the household, including cats or dogs, that lived with them in the home. Sixty-seven (93%) of the invited index cases submitted fecal samples, while 27  of these case households submitted samples from other members of the household (including pets).In these 27 households that submitted fecal samples from multiple household members, the index case person was predominantly female , and 12/27 (44%) were over 65 years old. All the index cases reported receiving antimicrobial treatment in the prior 6 months, including treatment for the index UTI. Twenty-three households  submitted samples from pets, 15 households  submitted fecal samples from other people, and 11 households  submitted samples from both pets and other people . Fecal samples from these 27 households were collected between December 2015 and January 2017 and were obtained between 31 and 180 days after the case UTI urine sample was provided .Enterobacteriaceae strain with an ESBL-/ACBL-producing phenotype, isolated from nine (6/18 dogs and 3/18 cats) individual animals (Table S1). Five of six positive dogs  were positive for ESBL-/plasmid-mediated ACBL-producing E. coli (from five households). In previous studies, raw meat diets and prior antimicrobial use have been identified as risk factors for ESBL-producing Enterobacteriaceae carriage in companion animals (P = 0.0006) (Table S1). However, there was no association between the consumption of raw meat and the carriage of ESBL-producing Enterobacteriaceae by pets (P = 0.23). Antimicrobial treatment was reported in four of the five dogs positive for ESBL-producing E. coli . Significantly more dogs  than cats  were positive for ESBL-/plasmid-mediated ACBL-producing E. coli (P = 0.02).Among the 23 households  that submitted fecal samples from pets, eight  households had pets that were positive for an  animals , 30. SigEnterobacteriaceae, isolated from nine  non-index case individuals. Two of these nine individuals had been treated with antimicrobials in the 6 months prior to the sampling of feces (as reported by the index case). None of the household contacts were reported (by the index case) to have had an MDR infection. In total, 15 households  had non-index case individuals (people or pets) that were positive for ESBL-/ACBL-producing Enterobacteriaceae, with 11  of these being households positive for ESBL- and/or plasmid-mediated ACBL-producing E. coli  households were positive for ESBL-/ACBL-producing  E. coli . These 1Enterobacteriaceae strain(s) associated with the households sampled, we cultured up to eight colonies per fecal sample as well as one colony from the index case urine sample. E. coli was the predominant species identified , with a Citrobacter species  and Enterobacter species  also being isolated. E. coli was the only bacterial species isolated that was shared between the index case and other members of the household (both people and pets). Short-read sequencing was carried out on all of the 125 E. coli strains from the 11 households that had an ESBL- or ACBL-producing phenotype (Table S2), and the draft whole-genome sequence assemblies were used to determine the phylogroup and sequence type of each isolate , papC , sfaC , afaC , kpsM , and iutA  , vat , fyuA , and chuA  (We next investigated the genetic relatedness of these strains by performing whole-genome multilocus sequence typing (wgMLST) for all 125 ustrated . Isolate25; 78%) , as well25; 49%) .E. coli isolates were resistant to cefpodoxime, in agreement with their ESBL- or ACBL-producing phenotype (Table S4), and they all carried an ESBL gene (blaCTX-M) or an ACBL gene (blaCMY or blaDHA-1) , and in HH64, this gene was associated with the index urine ST963 isolate and a dog ST2541 isolate. An MDR phenotype was observed in 87 isolates , and an MDR genotype, where genes associated with resistance to three or more classes of antibiotics were detected , was observed in 106 isolates   . No coliE. coli isolate were compared to a draft assembled reference genome selected from that household (Table S6). These comparisons were made using core single nucleotide polymorphisms (SNPs), and the resultant trees for individual households are presented in E. coli ST131 isolates across four households  that carried ESBL- or ACBL-producing Enterobacteriaceae was higher than that in other case-index carriage studies, which has been reported to range from 8.0% to 36.9%  was higher than that reported in previous studies of healthy companion animals, which ranged from 0 to 20.5%  of the investigated households. However, this proportion varied according to whether the household contacts sampled were people or pets. In 50% (5/10) of the households with multiple people, clonal strains (strains with a difference of <10 SNPs) of ESBL-producing E. coli were cultured from more than one person in the household, whereas in 22% (2/9) of the households where pets were sampled, clonal strains were cultured from a person in the household and the pet. The results of this study are comparable to those of other studies, where the carriage of clonally related ESBL- or ACBL-producing Enterobacteriaceae has been found in a similar proportion of family members  and food . Although eating raw meat is a risk factor for ESBL-producing Enterobacteriaceae carriage in both dogs and cats  were those also found predominantly in human infections in New Zealand  would also be required for any assertions around the intraperson  transmission of resistance genetics to be made.Analysis of the genome sequences presented here suggests that horizontal gene transfer (via plasmids) between bacteria may have occurred in some individuals. Discrete plasmids were not assembled through the bioinformatics pipeline; however, large numbers of plasmid-associated genes (and related plasmid types) were identified and reported. Although plasmid-mediated gene transfer was not explored experimentally within this study, there is the potential for this to have occurred with the ACBL gene Enterobacteriaceae, results were used for a transmission model that calculated a 12% probability of household transmission of ESBL-producing Enterobacteriaceae from a positive person to a negative person in the home  after an introduction event or through exposure to the same source of AMR bacterial isolate. Although our study suggests that companion animals  are carriers of ESBL- and/or ACBL-producing E. coli, their importance is hard to assess, and they are likely to be less important vectors than other people living in the home. From a public health perspective, the findings from our study reinforce current guidelines on hygiene practices within households and the importance of considering the entire household in control measures to reduce the spread of AMR enteric pathogens.The results of this study demonstrate the sharing of the same ESBL-producing Human ethics for this study was granted by the New Zealand Health and Disability Ethics Committee (HDEC) under reference 15/CEN/47; this study was part of a larger prospective case-control study looking at risks for community-acquired UTIs. Animal ethics for sampling via rectal swab from cats was granted by the Massey University Animal Ethics Committee under reference 15/35.E. coli in the presence of pyuria (≥10 × 106 white blood cells/liter), and the persons were considered to have a community-acquired UTI.Index cases were recruited based on culture and antimicrobial sensitivity testing results of urine samples collected from persons suspected to have a UTI and submitted to Labtests Auckland  between 28 September 2015 and 5 September 2017. All urine samples came from the Auckland and Northland regions of New Zealand. Additionally, all of these samples had the growth of Enterobacteriaceae isolate, had no record of being hospitalized overnight in the previous 12 months, and did not reside in an elder care facility or rest home. Seventy-two index cases were invited to submit fecal samples from themselves, as well as from any other members of the household, including cats or dogs that lived with them in the home. Five declined to participate; for the remaining 67, information on age, gender/sex, as well as antimicrobial treatment and hospitalization/veterinary care for the previous 6 months was collected.Index cases were eligible if they were 16 years of age or older, had no previous detection of an ESBL- or ACBL-producing Bacterial isolates from index case urine samples were collected from Labtests Auckland. Fecal samples were collected by the participants, using a sterile fecal collection bottle. Pet fecal samples were collected either by direct sampling with a rectal swab , using an agar transport swab , or by the participant from the ground or litter box. Samples were processed by plating onto culture media, as follows: plain MacConkey agar , MacConkey agar with 1-mg/liter cefotaxime sodium , MacConkey agar with 1-mg/liter ceftazidime pentahydrate (Sigma-Aldrich), and chromogenic ESBL CHROMagar . Rectal swabs taken from cats were enriched in buffered peptone water for approximately 16 h at 35°C before being plated onto the culture media. The agar plates were incubated overnight at 35°C, and two morphologically different single colonies (from each agar type) were selected for subculture onto Columbia horse blood agar (Fort Richard Laboratories). Up to eight colonies were chosen for subculture from each fecal sample. Identification of bacterial species from both urine and feces was done using matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry .Isolates were tested for antimicrobial susceptibility and an ESBL-producing phenotype according to EUCAST guidelines, using a Kirby-Bauer disk diffusion assay , 53. IsoEnterobacteriaceae isolates (n = 131) were selected for whole-genome sequencing from 11 households where multiple household members were positive for the carriage of at least one ESBL- or ACBL-producing Enterobacteriaceae isolate. Extraction of genomic DNA was conducted using a QIAamp DNA minikit , and libraries were prepared using a Nextera XT DNA library preparation kit . Sequencing was performed using Illumina MiSeq 2 × 250-bp paired-end reads  and Illumina HiSeq 2 × 125-bp paired-end reads . Raw sequence reads were assessed for quality and processed , from which the plasmid type (determined using the PlasmidFinder database [v.2.0]) , prior [v.2.0]) , resista[v.2.0]) , and vir[v.2.0])  were ide[v.2.0]) .E. coli isolates included in this study was performed using the genome of an ESBL-producing E. coli strain (strain JJ1886) originating from a urinary tract infection as the reference genome (Initially, SNP analysis of the e genome . Individe genome . A Nexuse genome , 66 for e genome .PRJNA600954.The sequence reads generated from this study have been deposited in the NCBI Sequence Read Archive under BioProject accession number


The novel coronavirus 2019 (COVID-19) pandemic in the United States (US) prompted widespread containment measures such as shelter-in-place (SIP) orders. The goal of our study was to determine whether there was a significant change in overall volume and proportion of emergency department (ED) encounters since SIP measures began.This was a retrospective, observational, cross-sectional study using billing data from January 1, 2017–April 20, 2020. We received data from 141 EDs across 16 states, encompassing a convenience sample of 26,223,438 ED encounters. We used a generalized least squares regression approach to ascertain changes for overall ED encounters, hospital admissions, and New York University ED visit algorithm categories.ED encounters decreased significantly in the post-SIP period. Overall, there was a 39.6% decrease in ED encounters compared to expected volume in the pre-SIP period. Emergent encounters decreased by 35.8%, while non-emergent encounters decreased by 52.1%. Psychiatric encounters decreased by 30.2%. Encounters related to drugs and alcohol decreased the least, by 9.3% and 27.5%, respectively.There was a significant overall reduction in ED utilization in the post-SIP period. There was a greater reduction in lower acuity encounters than higher acuity encounters. Of all subtypes of ED encounters, substance abuse- and alcohol-related encounters reduced the least, and injury-related encounters reduced the most. The coronavirus disease 2019 (COVID-19) is an ongoing global crisis with far-reaching social consequences. First reported in Wuhan, China, in December 2019, COVID-19 quickly spread across that country, despite a government-mandated lockdown of Wuhan on January 23, 2020. 6The large-scale social impact of COVID-19 has not been seen since the influenza pandemic of 1918 when non-pharmaceutical interventions – banning large public gatherings, school closures, and voluntary quarantine of diseased households – were most notably implemented on a large scale to decrease disease transmission.16Since the implementation of SIP directives, there have been reports of a significant drop in emergency department (ED) volumes by 40–50%.35To date, there is limited literature assessing the impact of the current COVID-19 pandemic on ED volumes across various encounter types in the US. An accurate assessment of the collateral effects beyond COVID-19 infection is crucial to guiding current and future public health management. We sought to determine whether there was a significant change in overall volume and proportion of various types of encounters in the ED since COVID-19 containment measures began. This study was an epidemiological analysis using retrospective billing data across 141 EDs comparing numbers before and after the first SIP orders in the US on March 16, 2020.What do we already know about this issue?The coronavirus disease 2019 (COVID-19) pandemic resulted in widespread social distancing measures, leading to concern for decreased emergency department (ED) visits.What was the research question?Was there a change in overall volume and proportion of various types of ED visits following shelter-in-place (SIP) orders?What was the major finding of the study?Total ED volumes decreased, with the greatest reduction in low acuity visits and the least in drug- and alcohol-related visits.How does this improve population health?This study shows the link between SIP orders and ED use during the initial weeks of the COVID-19 pandemic.This study was approved by the Arrowhead Regional Medical Center Institutional Review Board. Using a retrospective, observational, cross-sectional design, we analyzed ED log and billing data associated with a physician services billing company. Select demographic information provided by hospital medical record data was used to supplement the ED log data, in addition to coded billing data on primary diagnoses and procedures. Each patient billing record could hold up to four diagnosis codes and four procedure codes. Charges encompassed the physician services billing portion of the patient ED encounter, not the hospital billing charges. Dates where SIP orders were instituted make up the pre- and post-SIP periods see .15 For tThe study data set consisted of billing data from January 1, 2017–April 20, 2020, which encompassed 26,223,438 encounters across 141 EDs in 16 states within the US. Hospitals represented seven of the 10 Centers for Medicare and Medicaid Services (CMS) regions. Because the study data set is at the encounter level, patients could be represented multiple times within the data set if they returned to the ED for care. Patient characteristics, such as gender, age, hospital disposition, type of provider seen during encounter (physician or advanced practice provider), and Emergency Severity Index (ESI) level for the encounter are presented in Categorization of emergent and non-emergent ED encounters was done using the New York University (NYU) ED visit algorithm (EDA).Emergent care represents care for an acute condition where ED care was required. Emergent-preventable care represents care where ED care was required for an acute exacerbation but could have been treated or prevented with ready access to primary care. Emergent-primary care treatable is care that should be administered within 12 hours of presentation, but care could have been safely and effectively delivered within a primary care setting. Non-emergent care represents an encounter where care was not needed for at least 12 hours. For the NYU EDA diagnostic categories, Alcohol represents care for alcohol intoxication-related care. Substance Abuse represents care for non-alcohol substance use  intoxication or complications. Injury represents care for trauma, such as accidents and lacerations. Mental Health represents care for various psychiatric disorders . Unclassified represents care for diagnoses that could not otherwise be categorized per above.The NYU EDA sets specific criteria for each category of ED encounter regarding how emergent the encounter is. We used hospital discharge dispositions from billing data to ascertain admission status. ED encounters with admit or transfer discharge disposition were counted as a hospital admission. Hospital admission was limited to patients who presented through the ED and did not include directly admitted patients.Descriptive statistics of patient and hospital characteristics are presented in The data shows that there was a shift in the types of patients who used the ED in the pre- and post-SIP periods. Women and patients in the 35–64 and 65+ age groups made up the majority of patient encounters overall. The percentage of pediatric encounters (birth–18 years old) decreased from 16.2% to 8.4% in the post-SIP period. The distribution of patients across ESI levels demonstrated a bell-shaped distribution both pre- and post-SIP periods, where the majority of cases had ESI levels between 2–4. However, ED encounters with ESI levels 1–3 were proportionally higher in the post-SIP period. There was an increase in the proportion of patients who had an admit or transfer disposition following an initial ED encounter in the post-SIP period, 23.6%, vs 20.3% in the pre-SIP period.Of the seven CMS regions represented in our study data, the largest proportion of ED encounters came from Region 9 (San Francisco) with 76.8% of total patient encounters for the study period. The majority of patient encounters occurred in hospitals that were minor teaching (49.1%) or non-teaching (19.0%) hospitals in urban locations. Hospitals that were non-profit, either religious-affiliated (15.6%) or other non-profit (33.9%), represented the plurality of patient encounters with the remaining encounters spread relatively evenly across county (7.1%), for-profit (8.7%), and hospital district (4.9%) hospitals. The remaining 29.8% of patient encounters occurred in hospitals that did not report hospital organization type.There was a significant reduction in the number of ED encounters in the post-SIP period. Overall, there was a 39.6% decrease . −40.8%, −38.5%) in all ED encounters compared to what would have been expected in the study period. The greatest decrease was seen in the non-emergent encounters (−52.1%), followed by emergent-primary care treatable encounters (−47.5%), emergent-preventable encounters (−43.0%), and then emergent encounters (−35.8%) . HospitaOur analysis demonstrates that, after SIP orders were implemented, there was a 39.6% reduction in overall ED utilization. There are several, well-publicized theories as to why such a pronounced drop in volume occurred. One reason might be a true reduction in disease burden, especially a decline in traumatic injuries, due to the SIP order. However, other factors certainly contributed. An April 2020 ACEP poll suggested that public fear of potentially contracting COVID-19 from a hospital visit deterred patients from visiting EDs for conditions that they would have sought ED treatment under non-pandemic circumstances.31The proportion of patients admitted or transferred from the ED was higher post-SIP (23.6%) compared to pre-SIP (20.3%). Additionally, there was an increase in the proportion of patients with higher acuity ESI levels presenting to the ED post-SIP. The proportion of ESI levels 1, 2, and 3 increased with respect to ESI levels 4 and 5 post-SIP. This would suggest that the patients presenting to the ED post-SIP generally had self-selected for more serious conditions as compared to pre-SIP, and more of the “missing” visits were associated with lower acuity complaints.There were also differences in regard to the age of patients presenting to the ED before and after the SIP. The proportion of pediatric patients (birth–18 years old) presenting to the ED declined from 16.2% pre-SIP to 8.4% post-SIP. Conversely, the proportion of older patients (>35 years old) presenting to the ED increased from 61.5 % pre-SIP to 68.8% post-SIP. It would be difficult to determine exactly why such trends were noted. One possibility is that a parent’s weighing of the risk exposure to COVID-19 in the ED vs the benefit of being evaluated, as it relates to the decision to bring their child to the ED, is different than that of an independent adult deciding on their own care. Also, despite recent literature suggesting a potential rise in non-accidental trauma due to increased stressors at home during the pandemic, non-accidental trauma remains difficult to identify and often is under-reported.42Our study found that all categories of ED encounters set forth by the NYU EDA experienced a significant reduction post-SIP compared to pre-SIP. The reduction seen in the most emergent group (emergent-ED care needed-not preventable) was smaller when compared to all other categories. Furthermore, we found that as the acuity levels increased, there was less of a reduction of ED utilization in the post-SIP period. Despite this, the observation of a 35.8% drop in emergent encounters is a concerning finding. The long-term consequences of this large drop in emergent ED encounters is difficult to quantify, but clearly could have the potential to be far-reaching. This significant reduction in volume indicates that the most emergent patients are foregoing necessary treatments, raising concerns for an increase in overall morbidity and mortality.34Interestingly, ED encounters related to substance and alcohol abuse experienced the lowest reduction in the post-SIP period. For example, substance abuse-related ED encounters dropped by only 9.3% in the post-SIP period, while alcohol-related encounters dropped by 27.5%. This effect may be explained by the previously well-documented relationship between large-scale disasters and increased drug and alcohol abuse. Studies that looked at previous large-scale disasters such as Hurricane Katrina, the 2004 Southeast Asia tsunami, and the 2001 September 11 attacks, all reported an increase in either drug or alcohol abuse.Similarly, the 30.2% decline in visits with psychiatric diagnoses was smaller than the decline in emergent (−35.8%) and non-emergent (−52.1%) visits. Several studies suggest that depressive disorders and post-traumatic stress disorder have increased as a result of COVID-19.On the contrary, injury-related ED encounters experienced the greatest reduction (−56.1%) between pre- and post-SIP. We suspect this may in part be explained by the fact that injury is heavily dependent on individual behavior, and that behaviors promoted by pandemic measures have made people more cautious and less prone to experiencing injury. There may have been fewer motor vehicle accidents because people generally drove less due to SIP measures. Similarly, there may have been fewer work-related injuries due to more people working from home.While the focus of this and several other recent studies has been on the alarming reduction of emergent cases presenting at hospitals during the post-SIP period, the other side of the coin is a reduction in non-emergent and emergent-primary care treatable encounters that are best treated outside of high-cost hospital EDs. It is likely that a large proportion of patients who would have presented to the ED as non-emergent and emergent-primary care treatable encounters chose to forego care entirely. Another research question is to what extent did those patients choose to receive care in non-acute settings, such as urgent care or primary care clinics.While the study results have high external validity given the breadth of patient encounter data from 16 different states in the US, wider generalizability to international health systems may be limited by the particular insurance-based/fee-for-service payment system that is characteristic of the US healthcare system. Furthermore, the study data had a large proportion of encounters from the CMS Region 9, which may impact generalizability to other regions of the US.There are several follow-up research questions that could be asked from these findings. Future studies could investigate whether inadequate access to primary care offices due to SIP-related closures affected ED utilization. Findings would have far-reaching implications on primary care preparations in anticipation of a possible “second wave” of SIP closures or future pandemic planning. Another interesting topic to explore is whether rates of substance and alcohol abuse, and any complications thereof, will increase as the COVID-19 pandemic unfolds. A future study might explore whether ED utilization was absorbed by telehealth encounters, and to what extent. Future survey studies could explore perceptions of ED care during the post-SIP period and whether there were substantial changes in behaviors, such as engagement in hazardous activities, to reduce exposure to injury and hospitalization. Additionally, the long-term impact of the pandemic on the public’s utilization of the ED for low-acuity visits should be assessed. Lastly, another important topic to explore is whether the delays in care due to not presenting to the ED correlated with an increase in morbidity and/or mortality, not directly related to COVID-19.There was a 39.6% reduction in all ED encounters in the post-SIP period across all ED sites. The largest proportional reduction in ED encounters came from preventable and non-emergent ED encounters that could most likely have been treated at primary care offices. However, the large reduction in emergent ED encounters may potentially have delayed treatment and increased mortality seen outside of the ED. Of the five diagnostic categories in the NYU ED algorithm, injury-related ED encounters had the greatest reduction (−56.1%). This is may be a result of less motor vehicle travel and fewer hazardous work activities that contributed to the prevention of injuries. Substance and alcohol abuse-related encounters had the lowest reduction in the post-SIP period , describing the relatively unchanging nature of these disorders in needing emergent interventions, or possibly related to increased substance use associated with the pandemic.


The use of endovascular treatments, including Pipeline embolization devices (PEDs) and coiling approaches (non-PEDs), has played an increasingly important role in the treatment of intracranial aneurysms. Despite multiple studies evaluating PEDs, a real-world evaluation of follow-up outcomes and costs remains to be completed.The Premier Healthcare Database (PHD), 2010–2017, was queried to identify patients with unruptured intracranial aneurysms treated endovascularly. Rates of readmission, retreatment, and cost at the same hospital were compared between patients who underwent PED and non-PED endovascular treatments of their aneurysms. One-to-three (PED–to–non-PED) propensity score (PS) matching was performed to adjust for potential case selection bias into the PED cohort, with covariates including age group, sex, Charlson Comorbidity Index (CCI) group, payor, region, and randomized hospital identifier.A total of 679 patients underwent PED placement and 8432 had non-PED treatments. Prior to PS matching, there were significant but minor differences in age  and sex  for PED and non-PED, respectively, but no differences in CCI (p = 0.08), length of stay (p = 0.88), or rate of routine discharge (p = 0.21). All-cause readmission/emergency department reevaluation rates in the two cohorts were similar at 30, 90, and 180 days and 1 and 2 years. Our results identified a significantly lower retreatment rate for PEDs at all follow-up time points over a 2-year period (range: 0.9–8.1%) compared with non-PED treatments (range: 1.7–11.6%). These findings remained consistent after PS matching: all-cause readmission/reevaluation rates were significantly lower in patients treated with PED at 90 days, 180 days, 1 year, and 2 years (p<0.001). Although the initial treatment costs were higher for PED at time of treatment (p<0.001), cumulative follow-up emergency department visit and readmission costs (inclusive of patients with no readmission and/or no retreatment) were significantly lower for patients with initial PED relative to non-PED treatment at 2 years (p = 0.021).These results suggest that PEDs may potentially reduce downstream retreatment rates and costs. Further work is required to improve identification of patient subgroups that could benefit from PED over non-PED treatments both initially and during follow-up. TM Embolization Device (PED) , in particular, has been a disruptive innovation in the field of cerebrovascular surgery for the treatment of intracerebral aneurysms [Intracranial aneurysms represent a relatively common intracranial disease, with a prevalence of 3–11% and rupture rate of roughly 3–5% per year –7. The rneurysms –15. The neurysms , 17.The Premier Healthcare Database (PHD) is a U.S. hospital-based all-payor database with detailed information on inpatient admissions that has previously been used in one study of PED treatment among patients with intracranial aneurysms . A signiThe PHD includes diagnosis, procedure, and product-level information pertaining to 108 million unique inpatient visits from 970 hospitals, which represents approximately 25% of annual admissions in the U.S. . HospitaNo Internal Review Board approval was required for this study because the data used for analyses were deidentified. Data were abstracted from the PHD from 2010 through 2017. International Classifications of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) code 437.3  and ICD10-CM code I67.1  were used to identify patients with an admitting or principal diagnosis of unruptured intracranial aneurysm. Patients were included if they were ≥18 years of age and underwent an endovascular treatment for an intracranial aneurysm . Patients classified by ICD10-CM codes 747.81  or Q28.3  were excluded because it was unclear whether a “true” intracranial aneurysm was present in the absence of further clinical detail from imaging. Finally, patients with diagnosis of intracerebral, intracranial, or subarachnoid hemorrhage during the hospitalization were excluded from analyses given the inherently different patient severity profile. Endovascular PED treatment and non-PED treatments  were compared. PED was identified via product names listed in the Chargemaster file, whereas the non-PED cohort was defined as the remaining patients meeting study selection criteria who had no evidence of PED treatment recorded. We were unable to delineate the specific non-PED treatment  due to limitations in the specificity of ICD9 and ICD10 procedure coding over the years of data evaluated, and limitations in sensitivity of product names for stent and balloon-related products listed in the Chargemaster file.Among the patients meeting the selection criteria, one PED patient was matched to three non-PED patients using a propensity score (PS) model with the nearest neighbor approach and caliper width of ±0.10 of the standard deviation of the propensity score. Covariates in the propensity model included age group, sex, Charlson Comorbidity Index , region, primary payor, and the hospital randomized facility ID. Patients were matched by facility ID to ensure comparison of patients initially treated within the same hospital, but with different treatment approaches, to account for hospital-specific variations in practice patterns and costs.Patient demographic variables included age, sex, CCI, and payor type. The length of stay and discharge disposition were summarized for the initial admission. Cumulative incidence of follow-up all-cause readmissions and readmission for embolization retreatment were evaluated at 30 days, 90 days, 180 days, 1 year, and 2 years, among patients returning to the same hospital. Given the primarily cross-sectional nature of the Premier Healthcare Database, only readmissions to the initial treatment hospital were captured.The total hospital cost of the initial admission and the readmission cost specific to retreatment were summarized by study cohort. Additionally, total follow-up costs for all readmissions (regardless of retreatment) were averaged through one- and two-year follow-up across the entire study cohort, regardless of whether a readmission occurred . Cost was defined as internal hospital costs (as opposed to charges or payment/reimbursement amounts).Continuous variables are reported as means ± standard deviation (STD) whereas discrete variables are reported as number and % of total. The comparison of statistical significance across cohorts was calculated with the t-test for normally distributed continuous variables, the Wilcoxon-Mann-Whitney test for skewed (cost) variables, and the chi-squared test for discrete variables. A p<0.05 was considered statistically significant. Sample selection and creation of analytic variables were performed using the Instant Health Data (IHD) platform . Statistical analyses were undertaken with R, version 3.2.1 .A total of 679 patients who underwent PED treatment and 8432 patients who underwent non-PED treatment  were identified . These gPrior to PS matching, no difference in all-cause readmission rate was seen at up to 2-year follow-up , Fig 1A.After PS matching, the 679 PED treated patients were matched to 1918 non-PED patients , Fig 1B.The mean difference in initial hospitalization cost between PED and non-PED treatment modalities was significant when comparing the cost of admission for the initial index embolization and when evaluating cumulative readmission and emergency department visit costs over 1- and 2-year follow-up . PatientIn this study, we found that patients who underwent PED treatment of unruptured intracranial aneurysms were less likely to require retreatment at 90 days after index aneurysm treatment, and this benefit lasted through 2 years of follow-up (range: PED: 2.7–8.1% vs. non-PED: 5.7–11.6%). These findings remained even after adjusting for patient risk factors via PS matching (range: PED: 2.7–8.1% vs. non-PED: 7.9–14.7%). Furthermore, there were fewer all-cause readmissions, which included emergency room visits or admission to the hospital because of aneurysm-related complaints or complications as well as other hospitalizations, among patients treated with PED. Finally, although initial treatment costs were higher for PED treatment , cumulative follow-up readmission costs at 2 years (inclusive of patients with no readmission and/or no retreatment) were significantly lower for patients with initial PED relative to non-PED treatment, reflecting the lower incidence of readmissions for retreatment in the PED group.The higher initial costs associated with PED also need to be viewed in the context of size and location of aneurysms, which cannot be captured through PHD data. Because the initial FDA approval for PED was for larger aneurysms, it is very likely that the PED group in our data had a much higher proportion of larger aneurysms relative to the non-PED group. PED has already been shown to be more cost effective for larger aneurysms even for procedure costs, with a 27.1% cost reduction per millimeter of aneurysm treated because of the higher cost of implants (stent(s), coils) with the increasing size of the aneurysm .This study represents a real-world, multicenter comparison of PED utilization for the treatment of intracranial aneurysms with coil embolization. Follow-up costs and readmission rates were factored as potential metrics to better understand these two treatment modalities. This study also demonstrated significant cost heterogeneity  for the use of PED and non-PED technologies. This variability of inpatient costs likely depends on specific patient factors such as aneurysm size and location as well as intensive care unit length of stay, but it opens the promise of further improving resource utilization to drive down costs and standardize care.The demographics of patients in this study reflect groups treated by endovascular therapy. The mean patient age and sex distributions were similar to previous trials of coiling or PED , 13, 15.Several studies have reported on the safety profile and efficacy of PED for the treatment of intracranial aneurysms. McDonald and colleagues used the PHD to analyze 279 patients with unruptured aneurysms who specifically underwent PED treatment from 2011 to 2013 . AdverseThe inclusion of follow-up in the calculus of treatment efficacy and cost has been recently described for PEDs. The PUFS (Pipeline for Uncoilable or Failed Aneurysms) trial showed complete occlusion at 1-year follow-up in 79 of 91 patients, with 6 of 107 patients having major stroke or death (the study’s primary safety endpoint) . Follow-Previous studies have examined the cost of PED and coiling treatments , 27, 29.The strengths of this study are that the PHD is a large, well-documented database that, by design, comprises a random sample of the population presenting to both community and teaching/academic hospitals in disparate regions of the country, making the findings more generalizable to the population as a whole than prior single-center cohort studies. The main limitation of this analysis is the cross-sectional nature of the PHD data set, which only allows for follow-up evaluation of patients returning to the same hospital where their initial treatment was performed. Given this limitation, our study may underestimate retreatment rates among both cohorts of patients. Recurrence after treatment is also more likely in larger aneurysms compared with smaller aneurysms . Given tFor unruptured aneurysms in a multicenter evaluation, these study results suggest a lower retreatment rate for patients after PED treatment compared with non-PED treatments. When controlling for confounding variables, there were also lower rates of readmission and emergency department reevaluation at 90 days, 180 days, 1 year, and 2 years after index aneurysm treatment. Despite higher initial costs for PEDs, cumulative follow-up emergency department and inpatient costs, inclusive of all patients regardless of readmission or retreatment status, were significantly lower at two years amongst patients treated with PEDs. The findings of our study using the multicenter PHD suggest not only an important role for PEDs in the modern armamentarium for intracranial aneurysms but one that may prove to be associated with less burden in terms of utilization of valuable healthcare and economic resources.


Participants with more severe motor impairment or more severe cognitive dysfunction improved their total Mini-BESTest scores after exercise. The ABC-C exercise intervention can improve specific balance deficits, cognitive-gait interference, and perceived functional independence and quality of life, especially in participants with more severe PD, but a longer period of intervention may be required to improve global cognitive and motor function.Few exercise interventions practice both gait and balance tasks with cognitive tasks to improve functional mobility in people with PD. We aimed to investigate whether the Agility Boot Camp with Cognitive Challenge (ABC-C), that simultaneously targets both mobility and cognitive function, improves dynamic balance and dual-task gait in individuals with Parkinson’s disease (PD). We used a cross-over, single-blind, randomized controlled trial to determine efficacy of the exercise intervention. Eighty-six people with idiopathic PD were randomized into either an exercise (ABC-C)-first or an active, placebo, education-first intervention and then crossed over to the other intervention. Both interventions were carried out in small groups led by a certified exercise trainer . Outcome measures were assessed Off levodopa at baseline and after the first and second interventions. A linear mixed-effects model tested the treatment effects on the Mini-BESTest for balance, dual-task cost on gait speed, SCOPA-COG, the UPDRS Parts II and III and the PDQ-39. Although no significant treatment effects were observed for the Mini-BESTest, SCOPA-COG or MDS-UPDRS Part III, the ABC-C intervention significantly improved the following outcomes: anticipatory postural adjustment sub-score of the Mini-BESTest ( Exercise is advocated as an adjunct to pharmacological therapy for balance and gait problems in PD3. However, recent studies have shown that mobility and cognition, particularly executive function and attention, are deeply interconnected and affect each other in PD4. For example, individuals with PD show loss of gait automaticity with increased attention to control balance and gait6. Slow speed and short strides during dual-task walking reveal loss of automaticity and functional mobility for daily living and suggests increased fall risk in people with PD7.Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor impairments. Although pharmacological and surgical interventions are the mainstay of treatment, the effect is frequently suboptimal in alleviating balance and gait impairments in PD8, integrated motor and cognitive training may increase functional improvement in individuals with PD11. However, few intervention protocols directly address deficits related to both gait/balance and cognitive dysfunction to improve functional mobility in people with PD3. People with PD frequently show impairment in executive function, such as set-shifting, inhibition, and updating, as well as sustained, selective, divided attention and attentional switching11. So, we designed a cognitively challenging mobility training that included training these aspects of cognition.Given the evidence of cognitive network involvement in mobility tasks and overlap between cognitive and motor function12. Such dynamic balance control requires complex planning of motor sequences, sensorimotor agility, ongoing evaluation of environmental cues and contexts, the ability to quickly switch motor programs when environmental conditions change, and the ability to maintain safe mobility during multiple motor and cognitive tasks. In fact, neuroplasticity is enhanced best with intensive, complex, rewarding activities. Therefore, by improving dynamic balance, we improve a critical aspect of mobility. In previous studies14, we found that people with PD in a group Agility Boot Camp program, but not people in individual therapy, or in a treadmill aerobic program, significantly improved stride velocity, gait variability, arm swing and trunk stability in gait.Mobility, the ability of a person to move safely in a variety of environments in order to accomplish functional tasks, requires dynamic balance control to quickly and effectively adapt locomotion, posture, and postural transitions to changing environmental and task conditions11 builds off our previously described Agility Boot Camp (ABC)13 program, incorporating elements to challenge both executive function/attention and systematic mobility progressions via simultaneous execution of demanding physical and cognitive tasks. This new ABC-C program was designed to add challenge to the impaired attention and executive functions known to be affected by PD  and relevant to mobility disability11.The Agility Boot Camp-Cognitive Challenge (ABC-C)We hypothesized that a 6-week ABC-C program can induce functional improvements in balance, dual-task performance, and cognition in individuals with PD. We also investigated whether baseline severity of motor or cognitive impairments were predictive of efficacy of the program.15.The trial flow is summarized in the consort diagram of Fig. p = 0.003).There were no significant differences between Exercise-first or Education-first groups in the rate of perceived exertion for exercise and for compliance. Moderate to heavy RPE for exercise was reported in both groups . Both groups showed moderately high compliance for the exercise and for the education interventions . The Exercise-first group performed at a higher exercise challenging level compared to the Education-first group at the end of the study  improved in both the DTCmotor and the DTCcog (p = 0.04) after Exercise. When stratifying for cognitive severity, participants with worse cognitive function (SCOPA-COG score <27) improved both DTCmotor on gait speed (p < 0.001) and stride length (p < 0.002) after Exercise. See Supplementary Tables The DTCp = 0.02, Table p = 0.1, Table The PIGD sub-score of the MDS-UPDRS III significantly improved after Exercise compared to after Education   Table , Fig. 2dp = 0.001 and p = 0.001, respectively) and their total PDQ-39 after Exercise , Fig. When stratifying for motor severity and cognitive function, we found that only the individuals with the less severe PD motor signs (MDS-UPDRS Part III < 40) or less severe cognitive signs (SCOPA-COG > 27) significantly improved both their MDS-UPDRS Part II  significantly improved in dual-task cost for gait velocity, as well as dual-task cost on cognitive performance after the ABC-C Exercise training. However, subjects with moderate-to-severe motor impairment (MDS-UPDRS Part III > 40) did not improve in either gait or cognitive dual-task cost. No instructions were given on which task to prioritize in the dual-task condition, so it is possible that subjects with preserved cognitive function learned to allocate more attentional resources to the cognitive task, whereas subjects with mild cognitive impairment required all their attention on the gait task. The difficulty of more severely affected people with PD to improve gait-cognitive interference with practice suggests a limited ability for those with more severe PD to compensate with frontal, attentional circuits for loss of gait automaticity. However, it is not clear if gait became more automatic for those who improved dual-task cost or patients became better at switching attention quickly for dual-tasking.26. In fact, as previously reported, people with PD often show motor learning at a slower pace and of smaller magnitude relative to age-matched individuals, therefore requiring longer training to attain and maintain motor learning28. Previous exercise studies that reported significant improvements in the Mini-BESTest total score, MDS-UPDRS, and falls generally lasted 6 months or longer31. Second, subjects in a group class were heterogeneous in their motor, cognitive, balance and gait deficits (including those with and without freezing of gait). Although attempts were made to customize the exercise progression level for each individual, the group of 6 per class may have limited the challenge for those with less severe impairments. Third, although subjects underwent exercise intervention in their “on” state, all outcomes were measured in their “off” state to exclude the effects of dopaminergic medication. This may have impaired fully evaluating the effects of intervention on daily life functional performance. Fourth, there was no washout period between the first and second intervention in this cross-over design, so we could not rule out a possible carry-over effects from the first interventions. However, sequence and period effects were nonsignificant. Fifth, only the immediate effects of exercise were evaluated as we did not collect data regarding long-term retention, nor falls, one of the most debilitating results of impaired mobility.In summary, although we demonstrated a potential advantage of adding cognitively challenging components to mobility agility training, there are several limitations in the current study that we need to acknowledge. First, the intervention was limited to only 6-weeks. This short duration of training might be insufficient to yield a clinically significant improvement as reported in other studies in people with PDDespite these limitations, the current findings suggest important implications for clinical practice by providing evidence supporting the idea that exercise simultaneously targeted on both motor and cognitive function can enhance functional abilities in subjects with PD. Future studies should investigate the effects of a longer interventions on long-term benefits of the ABC-C, particularly in people with PD who have more severe motor and cognitive impairments.32. Participants were randomized into either an exercise-first or an education-first (active control) intervention and crossed-over after 6 weeks to receive the other intervention without a washout period. Both interventions were designed to have the same frequency with the same group and were delivered by the same certified exercise trainers, who were experienced in working with people with PD. Outcome measures were assessed at three time points: (1) baseline, (2) midpoint, after the first 6-week intervention, and (3) final, after the second six-week intervention. Independent exercise and medications were kept as stable as possible throughout the trial.The study was a cross-over, single-blind, randomized controlled trial to determine the effectiveness of the ABC-C for individuals with PD. All participants were diagnosed by movement disorders specialists as having idiopathic PD based on the United Kingdom Brain Bank criteria15.Details are provided in the Consolidated Standards of Reporting Trials (CONSORT) flow diagram Fig. . SubjectThis work was approved by the joint Oregon Health & Science University (OHSU) and Veterans Affairs Portland Health Care System (VAPORHCS) institutional review board ethics committees and each participant provided written informed consent. This trial was registered on Clinicaltrials.gov (NCT02231073 and NCT02236286).Subjects were randomly assigned to either the exercise-first or education-first intervention by a computerized block randomization centrally held in the Research Electronic Data Capture (REDCap) database-scheduling mode. Randomization was implemented by an independent statistician using a block size of 12 subjects (6 in each intervention). After randomization, the exercise trainer (unblinded) notified the subjects by phone. The participants were blinded to our hypothesis and expected outcomes. The researchers who performed all baseline, midpoint and final tests remained blinded to group assignment throughout the duration of the study.15). Briefly, each station was engaged for 10–20 min with short rest periods between stations. Activity at each station was systematically progressed over 3 levels of difficulty for each participant by challenging: visual and surface conditions, restricting external sensory cues, increasing speed and resistance, by including: response inhibition or set-switching tasks, and by adding secondary cognitive tasks9.The exercises were designed as a circuit to challenge movement-skills known to be impaired in PD and included the following stations: (1) Gait training (2) PWR! Moves ©, (3) Agility course, (4) Lunges, (5) Boxing and (6) Adapted Tai Chi  but did not include education about exercise so subjects would not change their exercise habits during the control intervention. The education program was developed by our study team to be specific for people with PD and focused on self-management of care team development, sleep, nutrition, stress, mood and medication. Classes met with the same trainer for 80-minute sessions, once a week for six weeks. In order to match the dose of education intervention with exercise intervention, participants were also provided relaxation CD’s to use at home 6 times per week for 30 min at a time, for an overall education dose of 240 min per week.9.The education intervention was developed to teach people how to better live with a chronic disease. It would be inappropriate in the active, control intervention, to teach subjects about exercise, balance and falls as it would likely change their exercise and fall-risk behavior/habits during the study. We previously published the interventions and protocol for this studyCompliance was recorded at each session by the exercise trainer for both the Exercise and Education interventions. For the education arm, participants also recorded compliance for the relaxation sessions in a logbook. The trainer coded progression of exercise difficulty at the end of each week to determine the level of exercise progression for each participant. Additionally, participants stated their rate of perceived exertion  after each exercise session.33. The Mini-BESTest33 is a sensitive measure of dynamic balance and includes 14 items (a maximum and best score of 28). Secondary analysis included scores of the 4 balance systems within the Mini-BESTest: Anticipatory Postural Adjustments (APA), Automatic Postural Responses (APR), Sensory Orientation (SO), and Dynamic Balance (Gait)33. We hypothesized that APAs and Dynamic Balance during Gait would improve the most as these were a focus of the ABC-C program.All assessments were performed in the practical off levodopa state after 12-hour withdrawal of dopaminergic medication. The primary balance outcome measure was the Mini-Balance Evaluation System Test (Mini-BESTest)motor) calculated as the percentage change of gait speed measured without  and with the simultaneous cognitive task . The cognitive DTC (DTCcog) was calculated using the same equation considering the percentage of correct answers in reciting every other letter of the alphabet while the subjects were seated for two minutes (ST) versus while the subjects performed the 2-minute walk over a 7-meter length. In a dual-task condition, no instructions were given on which task to prioritize. Details on the protocol are published elsewhere32.Secondary outcome measures included measures of cognitive-gait interference, perceived mobility disability and quality of life and cognition. Cognitive-gait interference was measured with the Dual Task Cost on gait speed  was used to assess quality of life focused on mobility35. Cognitive assessment used the Scales for Outcome of Parkinson’s Disease-Cognition (SCOPA-COG)36.The Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS UPDRS- Parts I-IV) was used to measure disease severity and the postural instability and gait difficulty (PIGD) subscore was calculated to assess parkinsonian gait and balancen = 34, milder and Part III ≥ 40, n = 52, severe)37. For cognitive impairment, subjects were stratified based on the SCOPA-COG score 36.A secondary analysis investigated the effect of exercise intervention based on the severity of baseline motor and cognitive impairments of subjects with separate linear mixed models. For motor severity, subjects were dichotomized with the MDS-UPDRS Part III , and a linear mixed model was calculated using MATLAB R2018b . The statistical significance was set to p < 0.05 for all analyses.As this study was a crossover design, the treatment effect represents whether the change (delta) during the Exercise intervention differs from the change during Education intervention. A linear mixed-effects model was used including an indicator of treatment effect (Exercise versus Education), order effect (Exercise-first versus Education-first) and period effect (sequence of assessments) to determine whether the “difference in change” differed between Exercise and Education. In addition, the effect of Exercise and Education was expressed as the standardized response mean (SRM) for each clinical and objective measure. The SRM was calculated as the mean change between before and after each intervention period divided by the standard deviation (SD) of the changeFurther information on research design is available in the Supplementary InformationReporting Summary


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a viral respiratory illness initially described in Wuhan, China, and was declared a pandemic by World Health Organization (WHO) in 2020, and the disease is named coronavirus disease (COVID-19). SARS-CoV2 is known to cause fever, cough, fatigue, and acute respiratory distress syndrome. As more patients become infected, extrapulmonary manifestations came to rise and hypercoagulability is one among those. COVID-19 could predispose patients to both venous and arterial thromboembolic events which are commonly treated with unfractionated heparin or low molecular weight heparin (LMWH). The treatment of patients who develop heparin-induced thrombocytopenia (HIT) while being treated with heparin or LMWH for COVID-induced thromboembolic complications is challenging.We describe a patient admitted to the hospital with COVID-19 pneumonia, found to have a cerebrovascular event treated with unfractionated heparin. She also received therapeutic LMWH for anticoagulation on day 1 of presentation due to atrial fibrillation. She was diagnosed with HIT and was found to have a pulmonary embolism, aortic arch mural thrombus, and arterial thrombi in the lower extremities. As more recent studies showed HIT antibodies in COVID-19 patients who are naive for heparin-based products, COVID-19 may be an independent risk factor for the development of HIT. The role of COVID-19 in the development of HIT is uncertain. High vigilance is required to diagnose and initiate treatment for HIT early in the disease course as it can be life-threatening. In December 2019, cases of pneumonia of unknown etiology were first reported in Wuhan, Hubei province in China. The etiology was found to be viral in nature and called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . Along wA 65-year-old female with a history of chronic obstructive pulmonary disease, and hypothyroidism presented to the emergency department (ED) with shortness of breath which was progressively worsening two days prior to presentation. She also reported having a fever with a temperature of 38 degrees Celsius ( ͦC), chills, and nonproductive cough in the last two days. The patient denied exposure to sick contacts, recent travel outside the state, or recent immobilization. Her temperature on admission was 39 ͦC, blood pressure 132/80 mmHg, heart rate 110 beats per minute, respiratory rate of 18 per minute. Physical examination was significant for lethargy, bilateral rales on auscultation of lung fields. Her oxygen saturation was 88% while on 5 liters per minute delivered through nasal cannula so she was placed on noninvasive positive pressure ventilation. Chest X-ray showed bilateral interstitial opacities consistent with viral pneumonia. The patient tested positive for SARS-CoV-2. Laboratory results at the time of admission are presented in Table She was started on remdesevir and dexamethasone as per institutional guidelines for the treatment of COVID-19 viral pneumonia. A 12-lead electrocardiogram revealed atrial fibrillation with a ventricular rate of 120 per minute, so anticoagulation was started with low molecular weight heparin (LMWH) 1mg/kg dosing twice daily and rate-controlling medications were administered. 12 hours after admission to the hospital, right arm motor drift, facial droop, and dysarthria were noted. National Institute of Health Stroke Scale (NIHSS) was 3. Emergent CT of the head revealed age indeterminate lacunar infarct in the left basal ganglia, with no intracranial hemorrhage. CT perfusion study of head and neck showed occlusion of the supraclinoid segment of the left internal carotid artery (ICA) with occlusive thrombus extending into the proximal left anterior cerebral artery (ACA) and middle cerebral artery (MCA)  in anticipation of the revascularization procedure. The case was discussed with an Interventional neurologist and the decision was made not to proceed with revascularization due to low NIHSS. While the patient was being monitored in the stroke unit, on day 3 of admission, she developed new right-sided hemiplegia, aphasia with altered mentation. The emergent CT of the head showed an increasing size of the infarct within the left basal ganglia and corona radiata. CT perfusion showed stable left ICA/MCA occlusion, however, due to progressive symptoms she underwent emergent left ICA/MCA thrombectomy. The weakness improved after revascularization with an increase in muscle strength from 1/5 to 3/5 in both right upper and lower extremities. UFH was discontinued due to an elevated risk of bleeding post revascularization.On day 7 after the procedure, anticoagulation was restarted with LMWH due to coexisting atrial fibrillation and COVID-19 infection. At this point, the patient completed a 10-day course of remdesevir and dexamethasone and was saturating well with 3 liters per minute supplemental oxygen through the nasal cannula. two days after restarting anticoagulation, a stroke code was called due to sudden onset, left lower extremity weakness. CT perfusion of head and neck demonstrated new distal left M2 branch occlusion within the Sylvian fissure. Mural thrombi were noted in the distal aortic arch and descending aorta. A complete angiogram of the chest and abdomen was done to determine the extent of clot burden. CT angiogram of the chest confirmed the presence of mural thrombus . Revascularization was successful with three-vessel runoff and dopplerable pulses in the left lower extremity. Anticoagulation was subsequently switched to apixaban. The patient recovered from COVID-19 and was discharged to the nursing home for rehabilitation for stroke.SARS-CoV-2 infected patients present mainly with upper respiratory symptoms such as nonproductive cough, fever, myalgias, headache, and sore throat. Whereas most patients recover after having mild symptoms, some progress into severe pneumonia, septic shock, acute respiratory distress syndrome (ARDS), and multiorgan failure. Laboratory studies show normal or decreased lymphocyte count (60%) and elevated C-reactive protein due to active inflammation . InitialAs the virus infects more people, newer complications, mainly related to hypercoagulability are being noticed. In a study done in New York City on inpatient intensive care unit (ICU) and non-ICU patients on venous thromboembolic (VTE) prophylaxis, the percentage of thrombotic events were 29.4% and 11.5%, respectively, and included both venous and arterial thrombi . ZsuzsanHIT is a prothrombotic adverse drug reaction to heparin derivatives like UFH or less commonly LMWH. HIT develops due to the formation of platelet-activating IgG antibodies against platelet factor 4 (PF4)/heparin complex. HIT is an immune-mediated, life-threatening condition, with the development of unexpected thrombocytopenia and new arterial or venous thrombosis about a week after exposure to heparin derivatives . 4T scorAs previously mentioned, the virus enters the cell through ACE2 receptors and completes replication. An immune response is then triggered in the form of a cytokine storm in infected epithelial and endothelial cells. Cytokine storm is characterized by the tremendous release of proinflammatory cytokines like tumor necrosis factor-α, interleukin-6 (IL-6), interleukin-1β. Of these, IL-6 is the main mediator of cytokine storm in COVID-19 patients . EarlierCOVID-19 could be an independent risk factor for the development of HIT, though the mechanism is unclear. In addition, due to the high risk of thromboembolic events in COVID-19, anticoagulation with heparin is increasingly being used in hospitalized patients. It is very important to have a high suspicion for HIT in these critically ill patients as it can be life-threatening and early detection can lead to an improvement in patient outcomes.


Supplemental Digital Content is available in the text Endoscopic resection of superficial non-ampullary duodenal epithelial neoplasm (SNADEN) is a challenging procedure owing to the high recurrence rate and considerable incidence rate of adverse events.SNADEN accidentally found during a medical examination in a 56-year-old manThe patient was diagnosed as having a 20-mm-sized flat elevated SNADEN at the superior duodenal angle.First, we tried to perform conventional EMR (CEMR). However, the submucosal injection interrupted the endoscopic view and did not provide enough space for CEMR because of its angulated location. Therefore, we chose to perform endoscopic resection using the “loop-and-let-go” technique. Follow-up duodenoscopy after 2 days revealed post CEMR ulcer with suspicious remnant lesion. Underwater endoscopic mucosal resection (UEMR) was successfully performed 3 months after the first session of endoscopic resection.Complete endoscopic en bloc resection and histological complete resection were achieved with UEMR. Follow-up duodenoscopy revealed no recurrence.Step-by-step endoscopic treatment with UEMR following loop-and-let-go technique may be a good strategy for SNADEN over 20-mm in diameter. However, this procedure needs a considerably prolonged procedure time and is associated with a higher incidence of adverse events such as perforation and bleeding.,6 In particular, the superior duodenal angle (SDA), an area with a narrow lumen and acute angle, makes complete resection difficult to perform. Recently, underwater EMR (UEMR) has been used in the treatment of challenging lesions in the duodenum and colon, including the appendiceal orifice and rectum reaching the dentate line. The treatment results seem good, providing high complete resection rate and low adverse event rate.–10 Recently, Iwagami et al reported the effectiveness and safety of UEMR in SNADEN when other efficacious procedure are unavailable.Recently, the incidence of superficial non-ampullary duodenal epithelial neoplasm (SNADEN) has increased because of the popularization of gastrointestinal endoscopic examination with the increasing need for diagnostic or screening purposes. Even if no definite treatment guidelines have been established regarding the indication for endoscopic therapy and selection of the treatment strategy, less invasive treatment modalities such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are preferred and thus frequently performed by endoscopists. EMR is the most common technique; however, the recurrence rate is high (5%–37%), and the procedure is accompanied by a considerable rate of adverse events such as bleeding and perforation.,13 To our knowledge, the loop-and-let-go technique has not been used in SNADEN, but it is known as a method of safe tumor removal, reducing the risk of bleeding or perforation.,13 Here, we report a case of complete resection of a SNADEN using UEMR after incomplete resection with loop-and-let-go technique.The loop-and-let-go technique is rarely used to remove large colonic lipoma or subepithelial lesions of the gastrointestinal tract.2http://links.lww.com/MD/F515). No adverse events occurred, including bleeding or perforation. We did not use any additional device for the prevention of adverse event. After 2 months, follow-up endoscopic and histological examinations revealed no recurrence in the site of the resected lesion . However, the submucosal injection interrupted the endoscopic view and did not provide enough space for CEMR because of its angulated location. Therefore, for the lesion, we instead chose to perform endoscopic resection using the loop-and-let-go technique . Follow-up duodenoscopy after 2 days revealed ulceration caused by the endoscopic resection and a remnant SNADEN (Fig. 3–5 ESD is performed for complete resection of duodenal neoplasms. However, this procedure needs a considerably prolonged procedure time with relatively higher incidence of adverse events such as perforation and bleeding.,6,14 Pocket creation method is another option for resection of duodenal neoplasm to prevent adverse events such as perforation, even though it showed relative high perforation rate and prolonged procedure time.This case demonstrates the effectiveness of UEMR for the treatment of SNADEN located at SDA. CEMR for duodenal lesions is often difficult because the duodenal lumen is acutely angulated and narrow, and the submucosa in the duodenum is fibrotic and highly vascular, resulting in poor lifting by submucosal injection. Moreover, inadequate injection sometimes makes snaring difficult because of luminal narrowing.,16 As we could not achieve complete resection using loop-and-let-go technique, we performed UEMR as 2nd session of endoscopic procedure. Nowadays, UEMR is selectively performed for the management of tumor of stomach, colon, and duodenum, especially in cases of difficult to preform CEMR or ESD due to location or submucosal fibrosis.–11,17 Binmoeller et al developed UEMR as a treatment for SNADENs, which showed a high complete resection rate and low adverse events rates for SNADENs over 20 mm in size. And Yamasaki et al also showed a good treatment outcomes for SNADENs under 20 mm in size. Recently, Iwagami et al demonstrated good efficacy of UEMR for 162 patients with SNADEN with short procedure time and no perforation. Previous reports for UEMR showed a good treatment outcomes with relatively short procedure time and low adverse events rate.,11,18 However, it depends on the tumor size of SNADENs; En bloc resection rate for ≥20 mm in size was 14%, while those for < 20 mm in size was 79% to 87%.,11 Median procedure time is 65 minutes for SNADENs ≥ 20 mm in size, while it decreases by 5.9 minutes for SNADENs < 20 mm in size.,18 UEMR has benefits for removal of SNADEN as follows;We tried to perform CEMR for SNADEN. However, we changed the method of endoscopic resection with loop-and-let-go technique, as the submucosal injection interrupted the endoscopic view and did not provide enough space for CEMR. Endoscopic resection using the loop-and-let-go technique is rarely used to remove large polyps or subepithelial lesions, which may avoid possible thermal injury that leads to bleeding or perforation.1.superficial lesions float up into the snare as protruding lesions in underwater conditions,2.the duodenal angles become obtuse,3.the narrow duodenal lumen is constantly distended.4.The underwater resection decreases the thermal damage to the duodenal wall, which helps to prevent delayed perforation, and5.the resection plane by UEMR is superficial, in which submucosal vessels usually remained within the resection wound, whereas the submucosal vessels were disrupted in CEMR.,11,18 As UEMR has been performed recently, long-term follow-up outcomes are required to validate the efficacy and safety for UEMR.However, there are reports of delayed bleeding, water intoxication syndrome, and aspiration pneumonia, which requires attention.We performed step-by-step endoscopic treatment with UEMR following loop-and-let-go technique for SNADEN over 20-mm in diameter. Even though we could not achieve complete resection using Loop-and-let-go technique, the size of SNADEN was reduced, which might have contributed to the success of the second session procedure with UEMR.4Step-by-step endoscopic treatment with UEMR following loop-and-let-go technique may be a good strategy for SNADEN over 20-mm in diameter.DHK performed the UEMR. EC performed endoscopic resection using the loop-and-let-go technique, CHP, HSK, SKC, and JSR collected the patient's data and contributed to the writing of the manuscript. DHK and SYP designed the research study and wrote the manuscript.


Background and purpose — Pooling data of studies evaluating total knee arthroplasty migration using radiostereometric analysis (RSA) may be compromised when the RSA method used would influence estimated differences between groups. We therefore reanalyzed a marker-based RSA study with model-based RSA to assess possible limitations of each RSA method, including insert micromotions in modular TKA and their effect on estimated group differences.Patients and methods — All patients had received a cemented Triathlon implant  with either an all-polyethylene (n = 29) or a metal-backed (n = 28) tibial component. The latter group was reanalyzed with model-based RSA. Precision of each RSA method was calculated using double examinations. Bland–Altman plots were constructed to determine the limits of agreement between the 2 RSA methods. Polyethylene insert micromotion was quantified by measuring migration with respect to the metal tray. Finally, analyses of the original study were repeated with the model-based RSA results.Results — Systematic differences were found in translations between marker-based and model-based RSA as a result of different reference origins being used for migration calculations. Micromotions of the polyethylene insert within the metal tray were negligibly small. Mean migration results were comparable between marker-based and model-based RSA when using the same reference origin, even though conclusions on individual patients may differ between RSA methods due to various types of measurement error .Interpretation — At least for the studied TKA design, pooling mean migration data of different RSA methods appears justified. For translations, however, adjustments should be made to correct for differences in reference origin. Migration patterns of individual patients may differ as a result of distinct types of measurement error. Due to the high accuracy and precision of radiostereometric analysis (RSA), late loosening of new implants can already be predicted with 2-year RSA results on small patient numbers  on implant migration of cemented metal-backed versus all-polyethylene tibial components in total knee arthroplasty (TKA) using the Triathlon TKA system   and analyzed using Model-based RSA software version 4.1 . For marker-based RSA analysis 5 tantalum markers (0.8 mm in diameter) were inserted during surgery, after drilling appropriate holes, at standardized positions in the polyethylene of both tibia designs. 2 markers were placed posteriorly, 2 anteromedially/anterolaterally, and 1 anteriorly. The number of markers available for migration calculations could differ over time due to marker occlusion . Marker-We first estimated differences in model-based analyses with 2 different reference origins, i.e., the reference origin in the geometric center of the model versus the geometric center of the polyethylene markers, using regression analysis. Bland–Altman plots were constructed to determine the limits of agreement between the two RSA methods  and registered at isrctn.com (ID: ISRCTN04081530). All patients gave informed consent. The costs of the RSA radiographs made for the original study were supported by Stryker. The sponsor did not take part in the design, conduct, analysis, or interpretations stated in both the previous and current manuscript. The authors declare no competing interests. Double examinations were performed in 21 metal-backed components at 1-year follow-up to determine the precision of the RSA measurements. Model-based results were less precise in rotations, especially about the longitudinal axis .Regression analysis revealed that with (1) routine model-based RSA versus (2) model-based RSA with the reference origin in the geometric center of the polyethylene markers, the transverse, longitudinal, and sagittal translations were overestimated by 29% (CI 25–32), 7% (CI 0–13) and 26% (CI 24–28), respectively  of the original report . However, 2 additional metal-backed components showed continuous migration based on the model-based analysis. In both cases, the increase in MTPM in the second postoperative year was likely the result of a sudden increase in rotation about the longitudinal axis due to model-fit inaccuracies, as all other parameters remained stable (data not shown).Supplementary data).The other RSA parameters showed comparable between-group results when repeating the analysis with model-based migration values, except for translations along and rotations about the longitudinal (y-)axis, again, due to model-fit inaccuracies (Supplementary data).In this trial, 2 surgeons performed the surgeries. When stratifying the results by surgeon as performed in the post hoc sensitivity analysis of the original report, the observed difference in MTPM in favor of the all-polyethylene design was smaller and not statistically significant. Repeating this sensitivity analysis with the model-based measurements resulted in similar conclusions  (Hansson et al. A limitation of this study is that we compared the results of only one tibial component design. As the precision of model-based RSA depends on the shape and accuracy of the fitted model (Kaptein et al. In summary, systematic differences in translations between marker-based and model-based RSA analysis disappeared when adjusted for the different reference origins being used for migration calculations. Micromotions of the polyethylene insert within the Triathlon metal tray were at most negligibly small. Mean migration results of model-based and marker-based measurements were comparable between groups when using the same reference origin, even though migration patterns of individual patients may differ between RSA methods due to various types of measurement error. supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674.2019.1605692The study was designed and coordinated by KH and STL. Data collection was performed by KH. Statistical analysis was done by KH, PM, and BK. KH, PM, LK, RN, STL, and BK interpreted the data and wrote the initial draft manuscript. All authors critically revised and approved the manuscript.The authors are grateful to Håkan Leijon for providing the marker-based RSA measurements and for his valuable help in performing the additional model-based RSA measurements.  Acta thanks Raed Itayem, Maiken Stilling and Lars Weidenhielm for help with peer review of this study.