The COVID-19 pandemic has strained health care system resources and reduced the availability of life-sustaining and medical-grade personal protective equipment (PPE) though the combination of increased demand and disrupted manufacturing supply chains. As a result of these shortages, many health care providers have temporarily used largely untested, improvised PPE (iPPE). Lack of quality control for makeshift PPE and frequent repurposing of used items to conserve supplies increase both the risk of provider infection and nosocomial spread to uninfected patients. One strategy to reduce risk of infection and preserve existing equipment is the implementation of secondary barrier devices placed directly over patients or providers. The authors describe an inexpensive, disposable, positive-pressure head isolation unit that can be rapidly constructed from materials readily available in nearly all health care settings for under five US dollars. The unit was successfully deployed in Taiwan during the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak, and again during the COVID-19 pandemic. The iPPE worn directly by the health care workers (HCWs) can be donned prior to patient contact in the presence of an air source. This strategy may be more protective than a covering placed over the patient in an aerosol-generating environment, which requires the HCW to be in close contact with the patient prior to securing the protective device. In May 2003, two resident physicians in a Taiwanese hospital were infected and subsequently died after contracting Severe Acute Respiratory Syndrome (SARS) while intubating a patient who was not known to be infectious. Positive-pressure airway devices, such as powered air-purifying respirators (PAPRs), were cost-prohibitive to implement on a large scale and not widely available during the SARS outbreak. The authors describe an inexpensive, disposable positive-pressure head isolation unit, called a Positive-Pressure Environment Disposable Shield, or PEDS, that was conceived in 2003 to reduce health care worker (HCW) and nosocomial infection risk from exposure to a novel virus.2 This is particularly concerning for novel and deadly viruses prior to effective therapeutic and vaccine development, since everyone is susceptible and is therefore at risk of infection and subsequent death. While the need for PPE to protect against droplet versus aerosol transmission may initially be unclear for a novel virus,3 HCWs performing AGPs must don aerosol protective PPE to ensure adequate protection in either case.Aerosol-generating procedures (AGP), such as intubation, are associated with increased risk of virus transmission to HCWs, even when they are wearing appropriate personal protective equipment (PPE).The COVID-19 pandemic has resulted in global shortages of medical supplies including gowns, N-95 respirators, and gloves, even in well-resourced countries. Additionally, health care systems in less-developed countries may have even less access to appropriate PPE for use in decreasing risk of nosocomial viral transmission. Many physicians and independent entities have resorted to constructing improvised PPE (iPPE) and medical devices that can be rapidly produced and used until medical-grade equipment can be replenished.The PEDS unit, which consists of materials readily available in most prehospital, hospital, and other health care settings, has been successfully tested and implemented in Taiwan during the 2003 SARS outbreaks and again during the COVID-19 pandemic to provide additional protection to HCWs from respiratory viral transmission  a highly transparent plastic bag larger than 36 cm by 45 cm (width by depth) that is placed over the HCW’s head; and 2) a nasal cannula attached to medical air or oxygen at 10 liters per minute (L/min)  respirator, surgical mask, or other facial PPE in addition to this head unit for added protection. Wearing a properly sized N-95 respirator will make the head isolation unit fit testing less necessary since the respirator will already provide sufficient protection for aerosolized droplets should the positive-pressure environment become compromised. In this case, the head isolation unit may be used to primarily reduce risk of N-95 or surgical mask contamination if supplies must be reused due to shortages.4 the authors recommend a modified procedure to check for leaks and ensure adequate positive air pressure. Select a challenge agent, such as one used for N-95 fit-testing. Ensure the wearer can taste or smell a dilute version of the solution. If the wearer reports no smell or a bitter taste upon direct exposure before fit-testing, use a different solution.5 Once a detectable challenge agent has been selected, assemble and generate the positive-pressure environment , is preferred for creating the positive-pressure environment, since repeatedly using high-flow oxygen for extended periods of time will greatly increase risk of hyperoxia. Medical oxygen may also not be readily available in large quantities, such as in the prehospital setting. However, medical oxygen is equally effective as compressed air for generating the positive-pressure environment and is acceptable for use on a short-term basis. Sources of compressed air and oxygen include wall outlets or portable cylinders whose gas contents range from 42L in a smaller bottle to 680L in a larger bottle at a pressure of approximately 15,168kPa .In addition to proper fitment before constructing and implementing the device, HCWs should consider adequacy of air flow to ensure safe and effective use. Compressed medical air, as opposed to medical oxygen (100% OTo ensure that the apparatus remains sufficiently inflated, even during a sudden inhalation that generates a negative respiratory pressure, the air flow must be sufficiently high at approximately 10L/min. When testing the dimensions listed above, 5L/min was the minimum amount necessary to prevent challenge agent detection; conversely, 15L/min was the upper limit of tolerated flowrate. Other factors that can increase airflow output include widening the air outlet or selecting a larger diameter of tubing. Therefore, for most applications, a rate 10L/min appears to provide sufficient positive pressure while mitigating the risk of discomfort or over-inflation.Providers who elect to use a mobile air source should be cognizant of the initial available air amount and how much they may need for the length of the procedure. Having inadequate pressure will result in the bag collapsing and compromise of positive-pressure airflow posing a risk of suffocation and PPE contamination. Tubing that is beyond one meter long may also inhibit airflow to the pressurized environment and could present an obstacle for other HCWs in the room. Ideally, HCWs should position themselves near the outlet or the air source. If the provider elects to use a mobile air source, the unit should be properly disinfected before next patient contact.Ad hoc implementation of iPPE has created a diverse array of solutions ranging from use of household items to repurposed commercial equipment. Experts have described the existing evidence, implications, and broader context of COVID-related PPE shortages.6There is an absence of published data related to the clinical efficacy of COVID-19 iPPE for protection of HCWs and prevention of nosocomial spread. In addition, data are lacking regarding effectiveness of devices created for the primary purpose of PPE preservation. 7 Notable iPPE devices include the COVID-19 intubation box and inflatable plastic coverings,9 both of which are patient-centered. One benefit to this approach is that it provides uniform protection for all HCWs in the room. In addition, these devices do not necessarily require fit-testing for the patient since they are designed to isolate aerosolized particles. However, a major disadvantage is that providers may be exposed to aerosols before the iPPE is applied to the patient. Furthermore, patient compliance, supply availability, and large size may present additional challenges.While the importance of HCWs wearing PPE is well-understood, protective equipment may also be placed on patients for the same prophylactic purpose.10 Therefore, it is imperative that any potential improvised provider-focused iPPE not only function well, but also be readily constructed using dependable and preferably disposable materials. The iPPE that utilizes positive pressure may provide additional protection compared to barrier devices that only cover mucosal membranes.6Conversely, provider-focused PPE represents a familiar option for health care providers in the form of respirators, gowns, and gloves. Provider PPE is a necessity and can only be supplemented by patient-focused PPE – not replaced by it. Popular forms of iPPE include repurposed gloves, mouth and nose coverings, and non-medical respirators to mitigate PPE shortages. Certain materials being used, such as cloth, likely provide inadequate protection against transmittable diseases.The limitations of the authors’ report are similar to those outlined in other presentations of iPPE. Many constructs are challenging to test due to a variety of factors that include unique assembly techniques, variable materials, difficulty measuring compliance of non-standard implements, and generally increased potential for cross-contamination. In addition, local, state, and national regulations will influence what forms of iPPE can be acceptably implemented in a given situation. All HCWs should ensure they follow guidance from the appropriate authorities before implementing non-standard equipment. Newer clinically verified interventions may also become widespread before PPE supply chains can be replenished, thus mitigating the need for certain innovations.The COVID-19 pandemic has necessitated the use of improvised medical equipment to protect both HCWs and patients. Providers in low-resource areas are at especially high risk of contracting and spreading the disease to each other and to patients if PPE is not readily available or must be reused. The simple design and low cost of PEDS, which uses components readily available in nearly all health care settings, means it can be rapidly constructed just prior to patient contact. Also, PEDS has the ability to help preserve valuable stock, such as N-95 respirators, surgical masks, and eye protection in addition to providing a secondary layer of positive-pressure protection for HCWs. Along with standard interventions, such as handwashing and respiratory and contact precautions, iPPE will continue to be a necessary additional line of protection for HCWs in a variety of health care settings globally, until medical supply chains can be replenished. As part of an overall strategy to augment all components of health system surge capacity, the PEDS unit has the potential to help protect and save the lives of frontline HCWs around the globe.


Sepsis continues to be a leading public health burden in the United States and worldwide. With the increasing use of advanced laboratory technology, there is a renewed interest in the use of biomarkers in sepsis to aid in more precise and targeted decision-making. Natriuretic peptides have been increasingly recognized to play a role outside of heart failure. They are commonly elevated among critically ill patients in the setting of cardiopulmonary dysfunction and may play a role in identifying patients with sepsis and septic shock. There are limited data on the role of these biomarkers in the diagnosis, management, outcomes and prognosis of septic patients. This review seeks to describe the role of natriuretic peptides in fluid resuscitation, diagnosis of ventricular dysfunction and outcomes and the prognosis of patients with sepsis. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) have been noted to be associated with left ventricular systolic and diastolic and right ventricular dysfunction in patients with septic cardiomyopathy. BNP/NT-proBNP may predict fluid responsiveness, and trends of these peptides may play a role in fluid resuscitation. Despite suggestions of a correlation with mortality, the role of BNP in mortality outcomes and prognosis during sepsis needs further evaluation. To date, 178 biomarkers have been studied in septic patients in recent years, with C-reactive protein and procalcitonin being the most commonly used tests in current clinical practice. Although these biomarkers can aid in diagnosis, determination of the severity and prognosis of sepsis, their specificity, and their prognostic implications have been described with wide variability.,16 Cardiac biomarkers have been evaluated previously in these patients to aid in prognosis and in the diagnosis of myocardial injury and/or dysfunction.-19 Cardiac troponin-T and I have shown a strong correlation between sepsis severity and outcomes and prognosis.,20 However, the role of commonly used natriuretic peptides, namely, B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), have not been thoroughly studied.Sepsis remains a major cause of morbidity and mortality, both within the intensive care unit (ICU) and outside, accounting for nearly US$17 billion of annual healthcare expenditures. however, there are limited summations of its correlation with ventricular function. Using a comprehensive literature search strategy, this review identified all pertinent studies evaluating the role of BNP and NT-proBNP in patients with sepsis. Specifically, adult human studies were reviewed and organized into a narrative style to describe the role of natriuretic peptides in septic cardiomyopathy, fluid resuscitation and outcomes and the prognosis of septic patients.This study sought to evaluate the existing literature on the role of BNP/NT-proBNP in the diagnosis and management of sepsis with or without concomitant septic cardiomyopathy. Prior reviews on this topic have focused on outcomes and prognosis in sepsis; The half-lives of BNP and NT-proBNP in plasma are 22 and 120 minutes, respectively. These natriuretic peptides are predominantly released in response to volume overload and myocyte stretching. B-type natriuretic peptide elimination occurs through several pathways, including natriuretic peptide receptor-C that clears natriuretic peptides from the circulation through receptor-mediated internalization and degradation and less so by neutral endopeptidases through the liver, lung, and kidney in its active form, whereas NT-proBNP is exclusively excreted by the kidneys.-29 The release of BNP and NT-pro BNP in sepsis is stimulated by multiple factors  in sepsis, although a recent meta-analysis did not demonstrate any correlation between LV systolic function and LV dimensions with mortality in this population. Formal echocardiography requires expert acquisition and interpretation that limits its generalizability and so a biomarker to detect early LV dysfunction could, therefore, be valuable for evaluating cardiac dysfunction in sepsis.Left ventricular (LV) dysfunction is noted variably in 20 - 50% of septic patients, which is likely due to differences in the timing of performing echocardiography and the severity of sepsis among these patients. Klouche et al. corroborated this finding at days three and four after admission, and patients with LV systolic dysfunction had significantly higher BNP values. In a cohort of cancer patients with sepsis, BNP on day two correlated with patients developing echocardiography-detected LV systolic dysfunction. In contrast to these studies that evaluated single measurements, Post et al. assessed BNP trends, demonstrating an inverse correlation between BNP and LV systolic dysfunction in patients with septic shock. Despite these correlations, it is important to note that echocardiography derived LVEF in sepsis should be interpreted with caution since it is a function of preload, afterload, and myocardial contractility, all of which vary in septic patients. Left ventricular stroke work index, a pulmonary artery catheter-derived parameter, may be a less load-dependent parameter of LV contractility and has been shown to be indicative of myocardial dysfunction in septic shock.,45 There are limited data in the current era due to decreased use of pulmonary artery catheters.,47Charpentier et al. first correlated BNP and LV dysfunction in septic patients, showing that patients with LV fractional area change < 50% and a higher end systolic LV diameter on day two had higher BNP levels than patients with a normal LV fractional area change. Papanakolaou et al. demonstrated that LVEF was not an independent predictor of BNP elevation in sepsis patients; rather, the severity of the illness seemed to be the primary determinant of BNP elevation. Several other authors also demonstrated elevated BNP levels in septic patients despite normal LV function.,50Other authors have shown that BNP levels are elevated in severe sepsis and septic shock regardless of the presence or absence of LV dysfunction.,52 and thus the correlation ability of BNP is subject to variability. Use of advanced imaging modalities such as tissue Doppler imaging, global longitudinal strain, and speckle tracking echocardiography may be more useful to evaluate the role of myocardial stretching in these patients that results in BNP release.In summary, BNP/NT-proBNP exhibits a strong correlation with LV function. However, the measurement of LV function in sepsis remains an ongoing debate, Diastolic dysfunction can potentially explain the etiology of troponin release in sepsis; however, similar mechanistic studies about the role of BNP in sepsis are not readily available. Elevated filling pressures in LV diastolic dysfunction may induce BNP release, and the prior literature has demonstrated that natriuretic peptides are typically lower in patients with preserved LVEF. Patients with LV diastolic dysfunction often have concomitant respiratory failure, necessitating the use of mechanical ventilation, which results in higher levels of BNP release.,35,55,56 Several studies have evaluated the correlation of BNP with diastolic dysfunction in septic patients, although they included small numbers of patients, and diastolic function was mainly reported as an ancillary outcome.,58 Sturgess et al. demonstrated diastolic dysfunction to be an independent predictor of BNP concentration in septic shock patients, and Lin et al. showed that BNP correlated with the severity of LV diastolic dysfunction in septic patients.,58 In contrast, in a study evaluating BNP trends in severe sepsis and septic shock patients, Mclean et al. revealed no apparent correlation between BNP and tissue Doppler velocities of diastolic function (p = 0.15). Based on the currently available data, it appears that BNP/NT-proBNP levels correlate with diastolic dysfunction. Further study of the BNP trends in diastolic dysfunction during sepsis is needed to evaluate its potential role in this increasingly recognized patient population since diastolic dysfunction has demonstrated strong correlations with clinical outcomes.,53Left ventricular diastolic dysfunction is increasingly recognized in modern practice and is noted to have a 20 - 57% prevalence in septic patients.,55 In sepsis, in addition to direct myocardial toxicity, increased nitric oxide, acute respiratory distress syndrome, hypoxemic pulmonary vasoconstriction and pulmonary hypertension contribute to worsening RV function.,59-61 BNP and NT-proBNP have been described in other disease states that can lead to acute RV failure, including acute respiratory distress syndrome, pulmonary embolism, and chronic obstructive pulmonary disease.,62,63 However, the specific role of BNP and NT-proBNP in sepsis-related RV dysfunction remains to be clarified.,48,49 McLean et al. demonstrated that BNP elevations in patients with severe sepsis and septic shock correlated with RV systolic performance more closely than with LVEF or LV end-diastolic diameter . Papanikolaou et al. demonstrated that both RVEF and LVEF were significantly correlated with serial BNP values, showing the likely interdependent nature of both chambers in this population.,55 B-type natriuretic peptide may play a role in the diagnosis and management of RV dysfunction in sepsis during the acute phase, analogous to high-sensitivity troponin. Importantly, RV dysfunction has shown stronger correlations with clinical outcomes at 6 months and one year, leading us to speculate on the role of long-term cardiopulmonary interactions.,64 There might be a role for serial BNP trending analogous to chronic heart failure, which remains an exciting new avenue for clinical and translational research. However, the contemporary data are limited and inadequate to evaluate the correlation between RV dysfunction and natriuretic peptides.Right ventricular (RV) dysfunction in sepsis and septic shock occurs in 30 - 60% of the population and is associated with worse short and long-term outcomes including mortality.,67 Only approximately 50% of unstable septic patients respond to a fluid challenge and identifying fluid responsive patients remains a significant challenge for clinicians. Dynamic measures such as respiratory variation of the inferior vena cava and changes in stroke volume after passive leg raising are more accurate in identifying patients who will increase their cardiac output in response to a fluid bolus.Early appropriate fluid resuscitation leads to better outcomes in sepsis, and this often requires a delicate balance between under-resuscitation and volume overload.-72 However, these data have not been reliably replicated in patients with undifferentiated shock or sepsis . In contrast, several authors showed no correlation between BNP and various parameters of volume status. Among surgical ICU patients, in which 42% had severe sepsis and septic shock, BNP did not correlate with circulating blood volume as measured by radioisotope dilution . Pirracchio et al. demonstrated that despite BNP > 1000pg/mL, 9 out of 11 patients with septic shock were still fluid responsive. Sturgess et al. showed a weak correlation between BNP and changes in stroke volume in septic shock patients . From the existing limited data, BNP does not appear to be a reliable marker of fluid status or responsiveness in septic patients. B-type natriuretic peptide represents a static variable and is unlikely to correctly estimate RV or LV preload conditions that undergo dynamic adaptation in sepsis. Studies incorporating a BNP-directed fluid management protocol may help elaborate on the role of BNP in fluid status determination in sepsis patients.B-type natriuretic peptide and NT-proBNP have been investigated as markers of volume status and fluid responsiveness. In patients with heart failure, BNP has been shown to be a useful marker of volume status, preload, estimated LV filling pressure, pulmonary artery occlusion pressure, and end-diastolic volume.r sepsis .. Brueckmann et al. evaluated NT-proBNP, also on day two of ICU admission, and noted a NT-proBNP of > 1400pg/mL was associated with a 3.9 times higher risk of mortality . Since these initial studies, many other investigators have evaluated the correlation of BNP and NT-proBNP with mortality in sepsis in various clinical settings  of 0.99 and 0.8, respectively.,90 In cancer patients who develop sepsis, NT-proBNP levels of > 6,624pg/mL predicted ICU mortality  on day two of ICU admission. Several other studies also reported BNP correlations with mortality at various time points during hospital and ICU stays.,85,89-91 Most studies included patients already diagnosed with a sepsis syndrome before inclusion, and therefore limited data are currently available for the association of BNP and outcomes prior to the onset of sepsis. One study evaluated patients who developed sepsis during their ICU stay (evolving sepsis) and demonstrated that BNP measured on day five was correlated with 30-day mortality in these patients.B-type natriuretic peptide and NT-proBNP have shown a varied correlation with short-term mortality  and 3. among the evaluated studies. In this systematic analysis, BNP assays, clinical endpoints, and vasopressor use varied markedly among the enrolled studies. Additionally, exclusion of pre-existing conditions known to elevate BNP and NT-proBNP differed among studies, with five of the 12 studies including cases with a combination of either pre-existing kidney and/or cardiac disease. Furthermore, two of the largest included studies were performed in the emergency room, representing sepsis patients at a markedly different time of resuscitation than later in their hospital course.,89Some studies have shown no correlation between BNP and mortality in sepsis patients. Among forty patients with sepsis and septic shock, Mclean et al. reported that BNP did not predict in-hospital mortality .Despite suggestions of a correlation with mortality, the role of BNP in mortality outcomes and prognosis during sepsis needs further evaluation in larger prospective studies. A single marker known to be elevated in a wide range of pathophysiologic states is unlikely to be a perfect fit as a prognostic marker in sepsis.,94 Khoury et al. demonstrated that BNP at admission was more predictive of short-term mortality than the Sequential Organ Failure Assessment (SOFA) score. In contrast, Ryoo et al. demonstrated a combination of BNP with the SOFA score resulted in better outcomes and prognosis in septic patients who either method independently. In surgically critically ill patients, the use of a bioscore combining BNP with lymphocyte percentage and procalcitonin showed a strong prediction for sepsis onset in this population.In recent years, some authors have used natriuretic peptides to develop novel scoring systems or demonstrate more accurate prognostic capacities than pre-existing scoring systems. In the evaluation of patients with dyspnea, a BNP level of < 100pg/mL has been used as a sensitive and specific value for ruling out heart failure. A level of > 400pg/mL suggests that heart failure is potentially a contributor to the patient's symptoms with 90% specificity. For NT-proBNP, a cutoff of 300pg/mL is used to rule out heart failure, whereas optimal 'rule-in' cutoffs vary, depending on age .-98The optimal cutoff of BNP and NT-proBNP to predict mortality in sepsis remains uncertain and varies between 32 to 681pg/mL for BNP and 400 to 13,600pg/mL for NT-proBNP. A recent meta-analysis was unable to determine optimal cutoffs for mortality outcomes and prognosis in patients with sepsis. Serial BNP testing may have greater clinical utility in outcomes and prognosis for patients with sepsis rather than as a one-time measure. Papanikolaou et al. recently demonstrated that persistently elevated BNP > 500pg/mL was a better predictor of 28-day mortality than isolated BNP values. Inability to reduce BNP to < 500pg/mL predicted 28-day mortality with AUROC 0.74 . Similarly, several other authors showed that improvements in BNP in serial measurements conducted over their ICU stay were associated with better survival, and variation between baseline BNP compared to 72 hours was significantly associated with 28-day mortality.,85 'Delta BNP' is a promising dynamic marker used to assess cardiovascular function and the outcomes of sepsis.Akin to acute heart failure, there may be utility in trending natriuretic peptides in patients with sepsis.,99 An inverse correlation has been shown between BNP and kidney dysfunction in critically ill patients. However, optimal cutoffs are yet to be defined in the septic population.,74,75 Several studies have shown elevated BNP levels in kidney dysfunction compared to patients with normal renal function despite similar cardiac function and hemodynamics.,100 Abnormalities in kidney function in sepsis remain a major confounder in studies evaluating the prognostic value of BNP in sepsis, as current studies variably exclude pre-existing chronic kidney disease and inconsistently adjust for acute kidney injury in the analysis. In septic patients, studies have shown conflicting results regarding correlations between BNP and serum creatinine; Roch et al. showed a weak correlation , whereas Ueda et al. showed no correlation. In addition to renal function, age and sex influence natriuretic peptide levels. Increasing age is known to cause elevated BNP and NT pro-BNP levels, although the mechanisms remain under investigation.,101 Women generally have higher levels of BNP and NT pro-BNP due to higher estrogen levels. Cutoffs based on age and sex have been suggested in primary care patients and heart failure populations but have not been validated in sepsis populations at the current time.Kidney dysfunction is a well-known cause of elevated natriuretic peptide levels and often confounds assessment in sepsis where AKI is seen in nearly 50 - 65% of patients.Natriuretic peptides are commonly elevated in patients with sepsis. Despite suggestions that their elevation can predict mortality and other clinically meaningful outcomes, studies are conflicting, and the role of these biomarkers remains unclear. The role of BNP and NT-proBNP in evaluating acute and chronic cardiovascular morbidity in sepsis and septic shock remains an exciting new avenue, and further research is warranted. Trends rather than isolated values may be more useful, and their use in conjunction with other clinical data may define a clearer role for BNP and NT-proBNP in sepsis.


BackgroundHeart failure is a clinical syndrome with significant morbidity, mortality, and financial burden. These factors are magnified in patients with associated comorbidities. Therefore, addressing such conditions is critical in decreasing healthcare costs and improving patient outcomes.Gout is a major comorbidity in patients with heart failure. Acute gout flares that occur in the context of acute heart failure exacerbations (AHFE) form an independent risk factor for increased readmissions or death. In this study, we characterized the frequency and outcomes of acute gout flares in patients treated with intravenous (IV) bumetanide for AHFE.MethodsThis single-center retrospective cohort study included 130 adult patients admitted in a tertiary-care hospital between August 2016 and June 2018. Chart review identified patients who were hospitalized for AHFE with International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code I50, received IV bumetanide, and developed an acute gout flare. Data were analyzed using the chi-square test for categorical variables and the two-sample t-test for continuous variables.ResultsThe annualized frequency of acute gout while receiving IV bumetanide for AHFE was 7.17%. Chronic gout patients who were on colchicine and/or allopurinol while hospitalized were less likely to develop acute gout while receiving IV bumetanide for AHFE compared with those taking neither medication . There was no significant difference in length of stay or 30-day readmissions between those who developed acute gout and those who did not.ConclusionsAcute gout flares occur with a notable frequency in patients hospitalized for AHFE who are administered IV bumetanide. It is important to continue patients’ outpatient gout regimens in an effort to mitigate acute gout flares during this time. Heart failure is a prevalent and ever-increasing public health concern that affects over five million people nationwide and is projected to cost $53 billion in healthcare expenditures by 2030 ,2. SymptGout, a clinical syndrome of joint inflammation resulting from the deposition of monosodium urate crystals, is a major comorbidity associated with heart failure ,7. FlareIn this study, we aim to determine the frequency of acute gout in patients treated with intravenous (IV) bumetanide for acute heart failure exacerbations (AHFE). Secondary outcomes include length of stay (LOS) and 30-day readmissions for any cause.This single-center retrospective cohort study included adult patients admitted to an urban tertiary-care hospital between August 5, 2016 and June 30, 2018. The study was approved by Temple University Institutional Review Board protocol #25611. Chart review was performed to identify patients who were hospitalized for AHFE with International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code I50, received bumetanide IV, and developed an acute gout flare. Patients were then selected through the application of specific inclusion and exclusion criteria  documented a clinical picture congruous with acute gout  and administered conventional treatment methods for acute gout including non-steroidal anti-inflammatory agents (NSAIDs), steroids, colchicine, urate-lowering therapies, and/or intra-articular joint injection with symptomatic improvement.Data collected from each chart included patient demographics , admission date and diagnosis, LOS stay, bumetanide administration , synovial fluid analysis, if obtained , and medical comorbidities, including known history of gout, chronic kidney disease (CKD), hypertension, diabetes mellitus, body mass index (BMI), and history of solid organ transplant . Chart review was also used to identify specific medications from each pharmacologic category of gout treatment agents. NSAIDs included indomethacin, diclofenac, ibuprofen, naproxen, meloxicam, celecoxib, nabumetone, sulindac and ketorolac. Steroids included prednisone, methylprednisolone, and dexamethasone. Gout therapies included colchicine, as well as urate-lowering therapies, such as allopurinol, febuxostat, and probenecid. For patients who developed clinical signs and symptoms of gout and given conventional treatment for acute gout by their treating physician(s), the date of symptom onset, the date of administration of the acute gout treatment , and the date of symptom resolution were identified. Lastly, data on readmission to the hospital for any reason within 30 days was also collected.Data were analyzed using the chi-square test for categorical variables or the two-sample t-test for continuous variables.A total of 137 patients were hospitalized for acute decompensated heart failure and received bumetanide between August 5, 2016 and June 30, 2018. After inclusion and exclusion criteria were applied, 130 patients were included in this study . Additionally, patients with a history of gout were more likely to develop an acute gout flare while receiving IV bumetanide than those without a history of gout . These findings are further described in Table An acute gout flare that occurred during treatment of AHF with IV bumetanide was associated with a non-significant increase in LOS by three days  during their hospitalization for AHFE had lower 30-day readmission rates for any cause (p-value =0.013, Table Gout is a significant yet often overlooked entity that has a notable association with heart failure. Patients with AHFE frequently receive loop diuretics such as bumetanide as a part of their therapeutic management, which increases the risk of acute gout flares by elevating levels of serum uric acid . Acute gPrevious studies have described this association between the use of loop diuretics and acute gout flares. In their large population-based longitudinal study, McAdams DeMarco et al. found that both loop and thiazide diuretics were independently associated with an increased risk of gout with a nine-year cumulative frequency of gout of 7% in those taking loop diuretics . A systeIn our retrospective cohort study, the annualized frequency of acute gout for patients receiving IV bumetanide for AHFE was found to be 7.17%. This frequency is on par with those documented in the literature . HoweverSecondary outcomes included LOS and all-cause readmission within 30 days. We found that patients who developed an acute gout flare while receiving IV bumetanide during AHFE had a longer LOS by three days compared with those who did not, though this difference was not statistically significant. However, the results surrounding readmission were more notable. First, we were able to corroborate the findings of other studies that patients with a history of gout have significantly higher readmission rates than those without a history of gout . AdditioThis study is limited by its small sample size and its single center and retrospective design. An additional limitation is that the diagnosis of acute gout, which is a central inclusion criterion for this study, was not necessarily crystal proven.In this study, we show that acute gout flares occur with a notable frequency in patients hospitalized for AHFE who are administered IV bumetanide. Patients with a known history of gout are particularly vulnerable to the development of acute gout flares in this context. The continuation of chronic colchicine and/or allopurinol yielded the opposite outcome. Further studies should investigate the use of other loop diuretics including furosemide to obtain a more comprehensive overview of incident acute gout flare in this population.


Among current smokers, the ARME and SSE were independent positive predictors of subsequent abstinence . For those currently abstinent, only the SSE predicted subsequent abstinence . GEE analyses showed different trajectories for the two measures, as well as between abstainers and smokers. In conclusion, the ARME is a reliable, valid measure with unique predictive utility for current smokers and a distinct trajectory among those who have successfully quit.The Abstinence-Related Motivational Engagement (ARME) scale was developed to assess motivation to remain abstinent after a smoking cessation attempt. The ARME demonstrated reliability and validity among a small sample of ex-smokers. This study expands the psychometric evaluation of the ARME and tests the ARME as a predictor of smoking status among a sample of participants quitting smoking. The parent trial tested the efficacy of a self-help smoking cessation intervention (N = 1874), with assessments every 6 months. Internal consistency and factor structure of the ARME was evaluated at each assessment to confirm use of the measure as designed. Discriminant validity was assessed by comparing the ARME to the Situation-specific Abstinence Self-Efficacy (SSE) scale via inter-correlations and prediction of future smoking status. Finally, the trajectories of both the ARME and SSE were compared among continuous abstainers and continuous smokers. A single-factor structure was observed at each assessment. Cronbach’s alphas ranged from 0.88–0.91 for the total sample. Correlations between the ARME and the SSE ranged from 0.38–0.47 ( Motivation to initiate a smoking cessation attempt and motivation to maintain abstinence can be conceptualized as separate constructs, independently influencing long-term cessation success . A smokiIn a preliminary development and administration study of the ARME, the 16-item version of the scale possessed excellent internal consistency and was associated with current length of smoking abstinence  = 120.8, p < .0001). The analysis also showed significant linear and quadratic effects for time , and a significant interaction with smoking group . Simple main effects for the abstinent group showed a significant positive linear and negative quadratic effect for time , which represents the large increase from baseline to 6 months to smaller increase after 6 months. Simple main effects for the smoking group showed a non-significant linear effect and a marginally significant positive quadratic effect , which represents the relatively flat curve with a slight downward trend to 18 months followed by a slight upward trend to 30 months.GEE analysis for average SSE scores found that the abstinent group had higher average scores , Structural Equation Modeling (SEM), and latent modeling techniques could assess item-specific properties, factor structure, and other dynamic features of the ARME as a measure and a construct.Although the ARME was originally developed to evaluate motivational engagement among individuals who had already achieved smoking abstinence, these results suggest that the clinical utility of the measure is strongest in the early stages of a quit attempt. This has important implications for smoking cessation treatments. For example, if ARME scores are low during contemplation, preparation, and initiation of a quit attempt, interventions should focus on increasing and sustaining motivational engagement . This sThis interpretation is consistent with the observation that abstinence-related motivation changes over time. That is, both successful and unsuccessful quitters showed a drop in ARME scores. Although this may reflect the mastery and automaticity of abstinence-related skills, it is also possible that stressors, triggers, negative affect, and other temptations to smoke could promote the development of “cessation fatigue” , 14. TheThese results should be interpreted within the context of methodological limitations. First, smoking status was determined via self-report and not verified biochemically. Biochemical verification is logistically and financially challenging, especially in nationwide trials like our parent study . Second,Results also suggest that the ARME may have limited capabilities in predicting relapse among those who are abstinent. In the present analysis, the ARME was a significant predictor of abstinence among those smoking, which suggests clinical utility of this measure with smokers. However, among abstainers, it may be difficult to identify those at risk for relapse to smoking using the ARME alone. As previously mentioned, perhaps more advanced psychometric evaluation techniques, such as IRT and latent modeling, could provide insight into response-specific indicators of relapse among those who have achieved abstinence. Finally, because of the nature of the parent trial, there was significant missing data among the full sample at each follow-up assessment, which may limit the robustness of the results reported herein.Our results indicate that the ARME is a reliable, valid, and psychometrically sound measure of abstinence-related motivational engagement among both smokers and successful abstainers. Although the ARME was correlated with a traditional measure of smoking cessation self-efficacy among smokers, abstinence-related motivational engagement appears to be independent of self-efficacy, with unique predictive power on future abstinence among smokers prior to cessation or after relapse. Enhancement of motivational engagement might be especially useful for smokers preparing to make or to sustain a quit attempt. Future studies should evaluate whether motivational engagement can be enhanced by focused interventions, and if this enhancement produces superior long-term abstinence or treatment adherence outcomes. Finally, the construct of abstinence-related motivational engagement should be evaluated among users of alternative nicotine and tobacco products  and users of other potentially addictive substances .


Wound healing is a complex physiological reaction in our body to tissue injury that can lead to the impairment of the original organ functions depending on the area of tissue injury. Many cell types participate in the wound healing process, including but not limited to, tissue resident cells, cells of the immune system, vascular cells, fibroblasts, and tissue progenitor/stem cells. However, the cellular and molecular regulatory mechanisms of wound healing are not yet fully identified. In the proliferation stage, granulation tissues develop accompanied by matrix deposition and neovascularization, which lead to proper regenerative responses including epithelialization. If this reaction is impaired, then scar formation and non-regenerative healing may occur, in which case many of aggravating factors, such as growth factors, inflammation, and tensile forces, are involved.This Research Topic consists of 11 published articles including 5 reviews, 2 mini-reviews, and 4 original research manuscripts. On behalf of the Topic Editors, we thank all the authors for their contribution. With their participation, we could draw a future perspective of wound healing research.Limandjaja et al. provide important knowledge regarding abnormal fibrosis, keloid. The review article details current research status and classification. The authors emphasized on several pathophysiological factors for keloids, such as inflammation-related environmental factors, keloid-prone topological factors and genetically predisposed individual factors. Defining the factors that contribute to the formation of wound lesion necessitates a demand for future basic and clinical research.Faster wound healing is always better for patients, and it is desirable that defected wound lesions heal to regenerate original normal tissue. If fibrous/fibroproliferative tissue develops as hyperplastic scar and keloid, respectively, aggravated appearance and uncomfortableness will affect the patient's quality of life. Although delayed wound healing and fibrous/fibroproliferative healing are contradictory biological reactions, both provide serious issues in wound healing in clinical practice. Matsumoto et al. utilized a gene expression analysis of human endothelial cells isolated from keloid and normal skin in patients by using magnetic-activated cell sorting and identified that SERPINA3 and LAMC2 were overexpressed in keloid endothelial cells. Overexpression of the indicated genes may affect keloid pathogenesis by inhibiting matrix degradation and prolonging inflammation. However, additional experiments should be performed to confirm this.In the process of keloid development, abnormal cellular functions have been investigated, and fibroblasts are a major cell type that are responsible for fibrosis-prone lesions. Although endothelial cells are also known to be a key player not only in inflammation, but also in fibrosis, their functional analysis in keloids has not been done. Barman and Koh summarized current knowledge of macrophage function in the pathogenesis of diabetes. Certain types of macrophages with pro-inflammatory and pro-healing phenotypes may play a dominant role during wound healing, whereas dysregulation of macrophage polarization could cause impaired wound healing. Thus, it is important to elucidate the relationship between macrophage polarization and the exacerbating factors in unhealed wounds.Macrophages are multifunctional innate immune cells with scavenging/phagocytosis as their main function. In addition, they play an orchestrating role in the wound healing process. Nurkesh et al. reviewed recent findings on using biomaterials, as drug delivery systems, to extend the activity of incorporated growth factors/cytokines for improving wound healing. Singampalli et al. described the roles of anti-inflammatory cytokine IL-10 and glycosaminoglycan hyaluronan in reducing scarring and improving tissue regeneration. A zwitterionic betaine-incorporated collagen sponge was newly designed for anti-oxidation and anti-inflammation by Chen et al.. Another approach in wound therapy is using a ubiquitin-specific peptidase 15 to enhance re-epithelization via an increase in keratinocytes that was reported by Zhao et al. in addition to the activation of TGF-β signaling pathway in fibroblasts. Development of new biomaterials/molecules may reveal a future strategy for wound healing therapy.New and effective biomaterials for wound therapy are desirable, which may lead to more effective treatment of unhealed wounds. In this Research Topic, Sato et al. described a novel population of mouse fibroblasts segregated by p75NTR expression and summarized their findings. The authors proposed that collagen degraded di-peptide, Pro-Hyp that arises in wounded tissue or from the blood via food intake, triggered fibroblast transition from a growth arrested subtype to a growth prone p75NTR-positive subtype. This new concept regarding collagen peptides in wound healing should be verified in the future.Collagen exists as an extracellular matrix protein and cellular scaffold in granulation tissue. However, its excessive deposition leads to the development of fibrous/fibroproliferative lesions in wound healing. Jiang and Scharffetter-Kochanek suggested that supplemented MSCs may act as an environment sensing adaptive cells in granulation tissues during wound healing. It was recently reported that microtube-based organelle called primary cilia senses chemical and mechanical signals by Hosio et al. This paracrine effect, rather than their self-renewal and differentiation capacity into several lineages, meet the changing demands during wound healing progression.The application of MSCs isolated from bone marrow or fat tissues has emerged as another approach for wound therapy. The review article by Marchesini et al. created a wound scar model in rats using talc. This animal model is useful for studying the pathogenesis of hypertrophic scar formation and to assessing potential therapy for treatment.Many types of animal models for wound healing are currently available. However, a scar forming model in rodents is rare. The collection of papers published in this Research Topic further contributes to our understanding of the wound healing process and describes new approaches to reduce scarring and improve wound healing. We hope these studies will stimulate further research in this challenging area of wound healing.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Uveal melanoma (UM) is the most common primary adult intraocular malignancy. This rare but devastating cancer causes vision loss and confers a poor survival rate due to distant metastases. Identifying clinical and molecular features that portend a metastatic risk is an important part of UM workup and prognostication. Current UM prognostication tools are based on determining the tumor size, gene expression profile, and chromosomal rearrangements. Although we can predict the risk of metastasis fairly accurately, we cannot obtain preclinical evidence of metastasis or identify biomarkers that might form the basis of targeted therapy. These gaps in UM research might be addressed by single-cell research. Indeed, single-cell technologies are being increasingly used to identify circulating tumor cells and profile transcriptomic signatures in single, drug-resistant tumor cells. Such advances have led to the identification of suitable biomarkers for targeted treatment. Here, we review the approaches used in cutaneous melanomas and other cancers to isolate single cells and profile them at the transcriptomic and/or genomic level. We discuss how these approaches might enhance our current approach to UM management and review the emerging data from single-cell analyses in UM. BAP1, SF3B1, EIF1AX, and SRSF2  is the most common primary adult intraocular malignancy  are still lacking and represent a notable gap in UM management. Emerging evidence suggests that analyses of circulating tumor cells (CTCs) and circulating free DNA  isolation, and immunomagnetic selection systems by Dynabeads or Miltenyi CD45 beads   and array-based CNV analysis   (Arozarena and Wellbrock, More importantly, this study showed that tumor-infiltrating immune cells express the checkpoint marker LAG3 rather than PD1 or CTLA4. LAG3 might, therefore, constitute a novel candidate for immune checkpoint blockade in patients with high-risk UM, who typically exhibit a poor response to PD1 and CTLA4 checkpoint inhibition Jindal, . This apIn a recent abstract publication by Rodriguez et al. , they idFor detecting CTCs, some of the previous melanoma CTCs markers used include melanoma-associated chondroitin sulfate proteoglycan (Ulmer et al., Similar to cutaneous melanomas, data from most UM studies have supported that the CTC count in UM correlates with the extent of hepatic metastasis and thus survival (Keilholz et al., One of the earliest CTC analyses in UM was conducted by Angi et al. . They usOthers have used real-time PCR to show that the expression of biomarkers, including tyrosinase messenger RNA and MelanA/MART1 in blood, correlates with the presence of CTCs (Keilholz et al., Tissue and liquid biopsy samples have been reported to show differences in molecular profiles in most cancers (Neumann et al., Based on the applications in cutaneous melanomas and other cancers, we propose a customized single-cell workflow for UM research . First, As UM is a rare disease, fresh tissue specimens are not readily available for research use; as such, many rely on melanoma cell lines (Gerber et al., Using this DEPArray single-cell image-screening approach , it was Although the genomic quality of this single-cell approach has not been validated, it is a proof-of-concept demonstration that such microdissection can be performed in UM, especially when there is a rare cell population that cannot be detected by routine flow cytometry.Despite the difficulties in performing scRNA-seq, scDNA-seq, and scCNV analyses on FFPE tissues, due to nucleic acid alterations after formalin fixation, recent studies have optimized such protocols to allow single-cell transcriptomic (Foley et al., Applying single-cell technology to UM has largely been restricted to identifying CTCs and limited to making correlations with clinical prognostic features. However, current single-cell technologies allow for transcriptomic and genomic analyses to be performed on isolated CTCs. By interrogating CTCs by scRNA-seq, scDNA-seq, and sc-CNV at the early and metastatic stages of UM and comparing the data with those derived from the original UM clone and/or the hepatic metastatic clone, it may be possible to elucidate the specific signature of malignant and non-malignant CTCs. The increasing success in detecting CTCs with the CellSearch platform suggests that early surveillance of circulating melanoma cells may soon become a reality, especially as CellSearch has already been Food and Drug Administration-approved for clinical use in other cancers.As mentioned, scRNA-seq analysis of the TME of UM has led to the discovery that UM immune cells express LAG3 rather than the traditional ligands used in immunotherapy. This finding, together with the demonstration of fibrotic collagenous bands surrounding mUM, explains why there is an immunosuppressive environment within these tumor nodules and why current immunotherapies are not successful in UM. Novel treatment strategies are, therefore, urgently required. Further interrogation of the TME in UM hepatic metastases and drug-resistant tumor cells may reveal novel targets and biomarkers for such new targeted therapies.Small sample sizes greatly limit the study power in mUM research. Moreover, single-cell tools are still not widely available in all institutions and countries. International collaborations that combine multicenter, single-cell research are thus crucial for the development and validation of novel findings. Such international collaborations might reveal genomic and transcriptomic differences that underlie the differences in UM survival and outcomes in different countries. Finally, forming an mUM research consortium will likely help develop standardized protocols that will ensure consistency in data production and a high standard of single-cell research.We propose that FFPE tissues can be used to overcome sample size limitations and generate pilot data before sourcing fresh tissues for validation. We have developed an FFPE single-cell approach using the DEParray platform that seems representative of the UM tumor microenvironment. Pitfalls associated with FFPE NGS analyses can be minimized with image-based single-cell isolation to review single cells before selection using brightfield or fluorescence images to eliminate false staining by debris or duplets and improve the quality of the isolated cells. Together with new techniques that improve the quality of FFPE RNA and DNA, this FFPE single-cell approach might constitute an alternative to help advance UM research.With these opportunities, we hope that the next decade of UM research will see an increase in single-cell-related studies that will lead to the development of clinically applicable tools for metastatic surveillance and new therapies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The Centralized Institutional Review Board of SingHealth provided ethical approval for the use of patient materials in this study. The patients/participants provided their written informed consent to participate in this study. Patients data and samples were anonymized after initial collection.AC designed the experiments and provided clinical material and data. MW, CC, and ML performed the experiments. MW and AC wrote the manuscript. All authors reviewed and approved the manuscript submission.WT and TL are researchers for A. Menarini Biomarkers Singapore Pte Ltd. AC received research funding from A. Menarini Biomarkers Singapore Pte Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Serologic studies are crucial for clarifying dynamics of the coronavirus disease pandemic. Past work on serologic studies  has made relevant contributions, but specific conditions of the current situation require adaptation. Although detection of antibodies to measure exposure, immunity, or both seems straightforward conceptually, numerous challenges exist in terms of sample collection, what the presence of antibodies actually means, and appropriate analysis and interpretation to account for test accuracy and sampling biases. Successful deployment of serologic studies depends on type and performance of serologic tests, population studied, use of adequate study designs, and appropriate analysis and interpretation of data. We highlight key questions that serologic studies can help answer at different times, review strengths and limitations of different assay types and study designs, and discuss methods for rapid sharing and analysis of serologic data to determine global transmission of severe acute respiratory syndrome coronavirus 2. Serologic studies are crucial for understanding current and future dynamics of the coronavirus disease (COVID-19) pandemic. In the past few months, much discussion about serologic studies and key issues with their design and interpretation has occurred. In this article, we discuss the questions that could be answered with these studies at different points in the epidemic and summarize the features and issues regarding study design, implementation of studies during an ongoing epidemic, and interpretation of the results. Discussion on the use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologic studies has largely focused on 2 questions: first, what proportion of a population has been infected?; and second, what proportion of a population is immune to disease or infection?First, for infections that elicit detectable antibody responses, serologic studies can detect past infection regardless of clinical symptoms. This capability is useful for understanding the extent of past transmission , panel ASecond, if measured antibody responses correlate with protection, serologic studies can be used to measure the proportion of the population that is immune. This information can be used to guide control policies, help identify populations that are still susceptible to epidemics, target treatment or vaccination trials, and target vaccination when available. Although much discussion around use of serologic testing to inform persons of their serologic status has occurred, crucial distinctions exist between the use of serologic information to estimate population-level versus person-level immunity. Person-level immunity information is currently fraught with scientific, ethical, and legal uncertainties, which we do not address in this article.Serologic studies will help answer these questions, but key unknowns persist regarding SARS-CoV-2 immunity and assay interpretation. Although estimating the proportion of the population that has been infected seems straightforward, careful consideration must be given to assay characteristics, the possibility for cross-reactivity with related coronaviruses, and the timing and magnitude of antibody responses. Timing and magnitude of antibody responses is particularly critical during a rapidly evolving epidemic, given the recency of infection for many persons.Understanding population- or person-level protective immunity requires knowledge of how protective immunity is related to past SARS-CoV-2 infection, the extent to which antibody types or levels correlate with protection, and how long immunity lasts. Serologic assays detect presence of antibodies but generally do not establish whether those antibodies protect the person; neutralization assays are required to gain a deeper understanding of the functional role of antibodies in immune protection. Inferring protection from serologic tests is possible only after thresholds of protection have been established. Therefore, 3 additional intermediate questions need to be addressed to understand the benefits of conducting serologic studies and to interpret studies: 1) What is the antibody response observed after SARS-CoV-2 infections of different severity? 2) What is the extent of cross-reactivity in antibodies in different populations and in different assays? 3) Can we define a protective antibody response (a correlate of protection)?https://doi.org/10.1101/2020.04.14.20065771). For SARS-CoV-2, questions 2 and 3 can be answered with careful analysis of the types of seroepidemiologic studies proposed in this article, but question 1 requires a different type of study, one measuring antibody responses at multiple time points after acute infections of different severities (https://doi.org/10.1101/2020.03.30.20047365), although more recent studies suggest that mild infections do lead to response . This matter will be critical for inferring past infection from serologic tests and so requires continued study in different populations.A recent review summarized what is known regarding these questions for other coronaviruses . These assays mainly fall into 3 categories: rapid tests; ELISA; and neutralization assays, such as plaque-reduction neutralization tests (PRNTs), microneutralization, or pseudovirus neutralization. Rapid, point-of-care tests generally use lateral flow immunochromatography and yield a qualitative (positive or negative) result. Despite their speed, ease of use, and amenability to mass screening, currently available rapid tests for SARS-CoV-2 have questionable accuracy. The World Health Organization (WHO) currently recommends that SARS-CoV-2 seroepidemiologic studies use IgG ELISA followed by confirmation of positive results with a PRNT  might be insufficiently specific to determine who in the population is immune . Specificity also might be a particular issue when infection prevalence is low .https://doi.org/10.1101/2020.05.15.20103275). The extent to which serologic testing missing current or very recent infections affects results will depend on the prevalence in the population and growth rate. The extra effort to collect a swab specimen might be necessary at epidemic peak but less necessary at the tail end of an epidemic.Even at the person level, interpretation of serologic testing is time-dependent because detectable antibody responses might only appear ≈2–3 weeks after infection. In an ongoing epidemic, a large proportion of persons will be recently infected and therefore will be negative by serologic testing. Conversely, a substantial proportion of previously infected persons might have detectable virus for several weeks , panel CFor different study types, the important assay characteristics are what sample is needed ; where the assay can be performed ; what resources, equipment, and reagents are needed; sample throughput and turnaround time; and cost. For public health, rapid and scalable approaches  are desirable. Such tests could also be useful for COVID-19 research in settings where restrictions on movement and social contact might limit the ability to collect samples. However, these methods need to be adequately validated before widespread use. The loss of information that comes with these tests might be offset by their ease of administration for some research questions but not for others.We assessed 3 seroepidemiologic study designs: cross-sectional studies, cohort studies, and targeted population studies. We also address the question of at-home or on demand testing. We provide a description of each type, the questions they could help answer, and issues with representativeness and implementation during the pandemic .Cross-sectional studies measure prevalence of antibody responses in a sample of the population at a single time point. These studies might be repeated at multiple time points  but not necessarily from the same persons. What inferences can be made about the wider population depends largely on how representative the study sample is. Studies with representative simple- or cluster-based random sampling of the population are the gold standard but require extensive planning, resources, and community engagement. Many other potential sources of serum samples for cross-sectional serologic studies are available, including residual serum samples from patients undergoing medical investigations and blood donation banks. These studies can be conducted more rapidly on routinely collected samples and might have access to historically collected, preepidemic samples available for analysis. However, they require different considerations of representativeness; residual serum samples reflect persons who are generally more ill than the general population and might come with biases inherent in clinical testing criteria, whereas blood donors tend to be healthier and do not include children. Moreover, routinely available blood samples might lack information beyond basic demographics, such as geographic information, underlying conditions, or potential risk factors for infection that could affect the epidemiology and transmission of SARS-CoV-2.Strict random sampling could also be relaxed by recruiting pragmatically through advertisements or from specific population groups but might be poorly representative and suffer from participation bias . Invariably, a trade-off exists between ease of sampling and ease of interpretation, and studies employing more representative sampling strategies will yield more valuable information.Prepandemic samples can be used to determine background non–SARS-CoV-2 coronavirus serologic profiles in populations. Repeated cross-sectional studies during the pandemic can give information on the proportion of a population infected, immune, or both at different time points and potentially different age groups . This approach might be less limited by restrictions on movements because of COVID-19.Recently, analytical methods for using serologic data to determine prevalence of past infection have progressed considerably, through an improved understanding of immunology and novel statistical methods. A substantial body of literature now exists on statistical and mathematical modeling methods for antibody data, alongside off-the-shelf software packages. Antibody levels vary over time for each infected person in a population experiencing a COVID-19 epidemic . ExistinIf SARS-CoV-2 infection is found to generate stable, consistent antibody dynamics after infection, then binary metrics are likely to give accurate estimates of seroprevalence, albeit with considerations of assay variability and the sensitivity of the chosen threshold , panel BHowever, if antibody kinetics after SARS-CoV-2 infection follow a more complicated trajectory, then models that capture additional immunologic mechanisms  will be required . Establishing a correlate of protection is difficult for any infectious disease, but challenges exist for novel pathogens, particularly during an outbreak with rapidly changing dynamics. When using the results from cohort studies as we have described, statistical analysis comparing preexposure immune responses in persons who subsequently have disease versus those that do not can provide information about whether an assay has characteristics that are useful for defining protective immunity or a correlate of protection. Similar work has been done for chikungunya and influenza viruses  to enable rapid sharing of genomic data and from platforms like Nextstrain (As proposed previously (Serologic studies at multiple stages of an epidemic could provide fundamental information for understanding the extent of past transmission, the current state of the epidemic, and future transmission. However, successful deployment of serologic testing will require optimization, validation, and proper interpretation of assays, which requires studies focused on these specific questions. Different types of epidemiologic study will be best and viable at different times during the outbreak and in different settings, and the biases of these study designs should be carefully taken into account in analysis and interpretation. Triangulation between multiple types of studies might also be of use. Current movement restrictions might constrain implementation of some study designs, so thought should be given to other study designs, although with consideration of their possible biases. The utility of serologic studies can be even greater if they are designed for optimal cross-location comparison. A platform to enable rapid data sharing, and therefore analyses across places and times, would also be very powerful.


This retrospective cohort study is aimed at determining the safety and efficacy between Femoral Open-Cutdown access and Percutaneous access with Endovascular Aneurysm Repair (EVAR) by contrasting perioperative complication rates. We hypothesized that the percutaneous approach is a better alternative for aortic aneurysm patients as it is minimally invasive and has been demonstrated to decrease the length of hospital stay.  We retrospectively reviewed data for patients undergoing EVAR between the years of 2005 and 2013. We then compared overall mortality, hematoma or seroma formation, graft infection, arterio-venous injury, distal embolization, limb loss, myocardial infarction or arrhythmia, and renal dysfunction. Results were demonstrated using a retrospective cohort study design to confirm the hematoma rate associated with EVAR open compared to percutaneous access. n = 49) or traditional open cutdown (n = 24). Percutaneous access resulted in significantly less hematoma formation when compared to the traditional open cutdown . Our analysis suggests decreased mortality rates associated with EVAR as compared to the Open-Cutdown method using Northside Medical Center's Study and the OVER Veterans Affairs Cooperative Study (p = 0.0053).  Our series involves 73 patients who underwent percutaneous access for EVAR ( Percutaneous access for EVAR is safe and effective when compared to Open-Cutdown access for aortic aneurysm patients. Percutaneous access was associated with decreased rates of in-hospital mortality, hematoma formation, graft infection, and respiratory failure. Aortic aneurysms have a well-established correlation with hypertension and atherosclerotic disease, and the treatment has evolved over the years. The advancement in surgical techniques to deliver grafts has vastly transformed the perception of aortic surgery. Endovascular Aneurysm Repair (EVAR) has essentially overtaken open repair of aortic aneurysms mainly due to the minimally invasive nature of EVAR as well as the decreased length of hospital stay . The femWhile the decision to perform traditional Open-Cutdown access or Percutaneous access is primarily due to physician preference, few large-scale studies evaluate the differences in the complication rates of both methods of access , 4. ThroA study performed by Cao and colleagues showed that Percutaneous access was associated with fewer complications, shorter hospital length of stay, and shorter procedure time . One of Physicians at our institution prefer to use the Percutaneous approach to femoral access for EVAR. This study intends to combine data from our institution with the data from prior studies to compare perioperative complication rates between Femoral Open-Cutdown access and Percutaneous access for EVAR with the hope of showing that the Percutaneous approach is an equally safe, or possibly better, alternative.We retrospectively reviewed data from Northside Medical Center and searched for patients undergoing EVAR between the years of 2005 and 2013, with most patients undergoing Percutaneous access and a small percentage having the open femoral cut-down approach. Complication rates that we compared included overall mortality, graft infection, hematoma formation, limb loss, renal impairment, myocardial infarction or arrhythmia postoperatively, and distal embolization. Each complication was diagnosed with the respective “gold-standard” test, such as using ultrasound for hematomas, to ensure accuracy. Immediate in-house perioperative complications and at a 30 day follow-up after discharge were evaluated. Our case series involves 73 patients. Of these, 49 underwent Percutaneous access for EVAR, and 24 underwent the traditional open cutdown. We compared overall mortality, hematoma or seroma formation, graft infection, arterio-venous injury, distal embolization, limb loss, the incidence of myocardial infarction or arrhythmia postoperatively, and associated renal dysfunction. We then used our statistical analysis to solidify the results of the hematoma rate associated with EVAR. Outcomes are provided in p < 0.059). One patient developed distal embolization  in the Open-Cutdown group, and two patients in the Percutaneous group developed similar results. In the Open-Cutdown group, one patient developed postoperative atrial fibrillation, and one patient developed renal dysfunction marked by decreased urine output and a rise in serum creatinine.Our results shown in One patient of forty-nine Percutaneous access patients experienced in-hospital mortality. This was an emergent ruptured EVAR, and the patient suffered severe hemodynamic instability due to exsanguinating retroperitoneal hemorrhage. Three patients in the Percutaneous group developed postoperative atrial fibrillation, and one patient had postoperative renal dysfunction.p = 0.0285). Separate analysis suggests that there may be decreased mortality rates associated with EVAR as compared to the Open-Cutdown method using Northside Medical Center's Study and the OVER Veterans Affairs Cooperative Study (p = 0.0053)  .Since 1991 . The safCurrent literature suggests that Percutaneous access to the femoral artery with ultrasound guidance is more advantageous than open surgical repair in the management of aortic aneurysms , 4, 13. Disadvantages observed in the Percutaneous method include distal embolization as well as pseudoaneurysms . Other fA fundamental objective to address is the incidence of forming large incisions in the groin with associated complications . The PerOur study showed precisely this that there is a lower rate of complications and mortality associated with percutaneous EVAR as compared to the Open-Cutdown procedure.Retrospective (NS study)Limited sample populationLocalized to one hospitalSelection biasPublication biasNot standardizedTheoretical relationship instead of a causal associationThe analysis includes two studies; the number of studies needs to be increased to decrease the bias furtherThe study limitations are as follows:We would like to do a larger meta-analysis on the data that is published and combined our data with the results from other multiple studiesWe would like to suggest that variables be made common among larger studies to enable a more integrated meta-analysis specifically analyzing hematoma, incision site infection, and other parameters that allow for broader comparison among numerous studiesWe would like to conduct a large-scale, prospective study, over a 5- to10-year periodFurther studies should be conducted evaluating set parameters to gather reliable data comparing open repair with EVAR surgical technique comprehensively:Overall, we found that there is a lower mortality rate associated with percutaneous EVAR as compared to the Open-Cutdown procedure, which is verified by analysis of the Northside Medical Center Study and the OVER study . The Nor