S. aureus (PVL-SA). Decolonization measures are required along with treatment of active infections to prevent re-infection and spreading. Even though most PVL-SA patients are treated as outpatients, there are few studies that assess the effectiveness of outpatient topical decolonization in PVL-SA patients.Recurrent skin abscesses are often associated with Panton-Valentine leukocidin-producing strains of We assessed the results of topical decolonization of PVL-SA in a retrospective review of patient files and personal interviews. Successful decolonization was defined as the absence of any skin abscesses for at least 6 months after completion of the final decolonization treatment. Clinical and demographic data was assessed. An intention-to-treat protocol was used.th treatment. A built multivariable Cox proportional-hazards model showed that the absence of PVL-SA detection (OR 2.0) and living in single person households (OR 2.4) were associated with an independently increased chance of successful decolonization.Our cohort consisted of 115 symptomatic patients, 66% from PVL-positive MSSA and 19% from PVL-positive MRSA. The remaining 16% consisted of symptomatic patients with close contact to PVL-SA positive index patients but without detection of PVL-SA. The majority of patients were female (66%). The median age was 29.87% of the patients lived in multiple person households. Our results showed a 48% reduction in symptomatic PVL-SA cases after the first decolonization treatment. The results also showed that the decrease continued with each repeated decolonization treatment and reached 89% following the 5In our cohort, topical decolonization was a successful preventive measure for reducing the risk of PVL-SA skin abscesses in the outpatient setting. Special attention should be given to patients living in multiple person households because these settings could confer a risk that decolonization will not be successful. S. aureus (PVL-SA) [S. aureus (PVL-SA) strains are methicillin-susceptible (MSSA) [S. aureus and additional PCR testing for the production of Panton-Valentine leukocidin by amplifying the encoding genes LukS/LukF [Recurrent skin abscesses in patients who do not have a predisposing condition are often associated with Panton-Valentine leukocidin-producing strains of (PVL-SA) –3. Altho(PVL-SA) , in Euroe (MSSA) . The verukS/LukF .S. aureus can make PVL-SA colonization time-dependent [There can be a considerable delay in diagnosis despite its typical clinical presentation with non-immunocompromised patients who suffer from recurrent skin abscesses. This results in multiple episodes of skin infections and often leads to the transmission of pathogens to close contacts , 2, 6, 7ependent , 11. ThiAfter the primary treatment of PVL-SA-related infections, secondary prevention requires topical decolonization , 12–14. Our cohort consisted of patients with recurrent skin infections combined with the detection of PVL-positive S. aureus (PVL-SA) as well as their close contacts who sometimes also displayed symptoms. All cohort members were seen in our outpatient clinic between December 2010 and August 2017. Recurrence of an abscess was defined as more than one abscess that required surgical drainage within a two-month period. Patients with a (predisposing) chronic skin condition, e.g. Acne inversa or severe atopic dermatitis, were excluded from the present study. In clusters with more than one symptomatic and / or PVL-SA-positive patient, the topical decolonization protocol was followed for all household members. In case of active PVL-SA skin infections, patients received a rifampicin-based dual antibiotic regime combined with TMP/SMX or as determined by antibiogram results. In addition, patients were advised to start a decolonization treatment at home after the resolution of the infection. Decolonization involved a 5-day standard decolonization protocol that included daily antiseptic washing of the whole body and hair with a commercially available octenidin-based product, antiseptic treatment of the oral cavity (octenidin-based), intranasal application of mupirocin, and extended hygiene measures including the washing of clothes at more than 60°C and disposing of personal care products [Success of the decolonization procedure was defined as a period of at least six months without a skin abscess or other SSTI following completion of the decolonization treatment. Decolonization was repeated in cases when skin abscesses recurred. The following variables were systematically evaluated in interviews to assess the factors that reduced the success of decolonization: age, gender, number of decolonization treatments, household size, number of close contacts to the index case, abscess localization, and phenotype of PVL-SA (MRSA or MSSA). A cluster was defined as individuals in the index patient’s immediate environment  who were also colonized or infected with PVL-SA. Household size was defined as the number of individuals living together in a household with the index patient.LukS/LukF was performed using PCR [All patients were screened for PVL-SA in nares, throat and wounds, if applicable. Swabs were cultivated on Columbia Agar with 5% sheep blood. Species identification and antimicrobial susceptibility testing were performed using a Vitek 2 system and applying EUCAST breakpoints. The detection of PVL sing PCR .In order to assess parameters influencing the length of time needed for successful decolonization, we performed a univariate Kaplan-Meier analysis and a multivariable Cox regression of all symptomatic patients, applying an intention-to-treat protocol. All analyses were performed using SPSS .Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki, national, and institutional standards. The study was approved by the local Ethics Committee . The study is based on secondary data that was generated for routine clinical care. Within this scope, written consent for treatment purposes and secondary analysis was provided by each patient. Consent for minors under age 18 was obtained from parents or guardians. The Ethics Committee waived the requirement for additional consent for this study.Sixty seven index patients with PVL-SA-positive recurrent skin abscesses presented to our outpatient clinics between December 2010 and August 2017. Altogether, they reported 128 close contacts (accounting for n: 195). 48 of 128 contacts reported recurrent skin abscesses. Of the remaining 80 asymptomatic contacts, 40 contacts participated in PVL-SA screening, revealing an additional 21 PVL-SA positive cases. The remaining 40 asymptomatic contact patients were not available for examination of PVL-SA .Taken together, of 155 patients and contacts, PVL-SA was verified in 118 cases (76%). One patient was colonized with both phenotypes, hence 27 MRSA (23%), 92 MSSA (78%) were detected.By the time of diagnosis (skin abscess due to PVL-SA), the patients’ medical histories showed a median of 4 episodes of skin abscesses (IQR 2–10) and a median delay of 5 months between first episode and final diagnosis (IQR 1–14). We found it helpful to calculate the average number of abscesses per month as an estimator of the severity of the infection and the psychological strain on patients. The result was a median of 1.0 (IQR 0.3–2.8). Common abscess sites included extremities (50%), trunk (47%), and head or face (42%), without any specific distribution pattern. Few patients (4%) showed invasive infections, such as necrotizing fasciitis, necrotizing pneumonia or bloodstream infection.Based on the patients’ past medical histories, many reported that they had undergone multiple antibiotic treatments and multiple episodes of surgical intervention before being diagnosed with skin abscesses from PVL-SA. 38 (33%) patients reported hospital stays for the treatment of their recurrent abscesses with a length of stay between 1 and 42 days (median 3 days). Following an intention-to-treat protocol, we analyzed all 115 symptomatic patients for successful topical decolonization. 77 (67%) received systemic antimicrobial treatment beforehand without relevant reduction in infection incidence. The median follow-up time was 15 months after the final decolonization treatment. After the first decolonization treatment, the number of symptomatic patients was reduced by 48% (56 patients) . 13 patiThe following parameters were considered in the Cox regression analysis: age, gender, number of decolonization treatments, single vs. multiple person household and phenotype of PVL-SA (MSSA/MRSA). Factors independently associated with a successful decolonization were living in a single household (in contrast to a multiple person household) and undetected PVL-SA in symptomatic patients .S. aureus are frequently associated with recurrent episodes of infection, delayed diagnoses, and eventually an increased risk of transmission often resulting in clusters of affected patients in close personal proximity [Skin and soft tissue infection caused by PVL-positive roximity –3, 6, 16roximity , 18.S. aureus in the past [Pathogen transfer within households has been described repeatedly as the dominant transmission route for community-acquired the past , 19, 20.S. aureus clones ‘ping-ponging’ between family members [Knox et al. stated that the degree of physical contact among household members and the amount of time spent at home determine the risk of transmission . This co members –22. ThesOur results show that symptomatic patients in which PVL-SA could not be detected have a higher chance of successful decolonization. Hence, this observation could be an indication that a low-level colonization with PVL-SA might facilitate the eradication process. Earlier studies of MRSA decolonization have shown that the success of eradication can be dependent on the localization of the colonization –25. In oIn the present study many patients reported a past medical history typical of PVL-SA patients–recurrent skin abscess that often required incision and drainage and reporting other affected patients in their immediate environment. PVL-SA-positive patients are often symptomatic for several months, before they are finally diagnosed and treated for PVL-SA , 26–29. The patients in our cohort were on average 29 years old, confirming earlier studies on patients with community-onset PVL-SA-associated skin abscess , 31. WheOur study has several limitations. This is a retrospective study on PVL-SA patients from a single institution. It represents the patient population from our area and mirrors the results of our locally established treatment procedures. All patients with an active infection were treated with an oral antimicrobial agent—at least once—parallel to topical treatment. This makes it impossible to determine the effect of the antimicrobial therapy on the decolonization results. However, considering the fact that 2/3 of our patients had received antibiotics without any topical decolonization and continued to suffer from recurrent skin abscesses argues against a major protective role of isolated antibiotic use in these patients. Patients in our cohort had a mean total of four skin abscesses in the five months prior to topical decolonization; after successful decolonization, all patients were asymptomatic for at least 6 months with a mean follow-up of 15.6 months.Our data shows that patients with skin abscesses associated with PVL-SA can be successfully treated with decolonization as outpatients, but they often require multiple attempts at decolonization. The delayed success of treatment of patients living in multiple person households suggests that decolonization treatment should be conducted simultaneously on all close contacts.S1 Database(XLSX)Click here for additional data file.


Supplemental digital content is available in the text. Pancreatic resection is associated with postoperative morbidity and reduced quality of life (QoL). A systematic literature review was conducted to understand the patient-reported outcome measure (PROM) landscape in early-stage pancreatic cancer (PC).Databases/registries  and conference abstracts (2014–2017) were searched. Study quality was assessed using the Newcastle-Ottawa Scale/Cochrane risk-of-bias tool. Searches were for general  and supplemental studies .Of 750 studies identified, 39  were eligible: 32 used QLQ Core 30 (C30) and/or QLQ-PAN26, and 15 used other PROMs. Baseline QLQ-C30 global health status/QoL scores in early-stage PC were similar to all-stage PC reference values but lower than all-stage–all-cancer values. The QoL declined after surgery, recovered to baseline in 3 to 6 months, and then generally stabilized. A minimally important difference (MID) of 10 was commonly used for QLQ-C30 but was not established for QLQ-PAN26.In early-stage PC, QLQ-C30 and QLQ-PAN26 are the most commonly used PROMs. Baseline QLQ-C30 global health status/QoL scores suggested a high humanistic burden. Immediately after surgery, QoL declined but seemed stable over the longer term. The QLQ-C30 MID may elucidate the clinical impact of treatment on QoL; MID for QLQ-PAN26 needs to be established. Therefore, it is important to understand the landscape of patient-reported outcome measures (PROMs) that can quantify and track QoL in these patients.Surgical resection is the only potentially curative option for pancreatic cancer (PC).17 However, in early-stage PC, it is unclear from the few available studies of QoL which PROMs are most commonly used and appropriate. A more thorough understanding of QoL in early-stage PC, including how it changes over time after surgery as well as the PROMs most commonly used to measure QoL, may help identify specific areas that have not been fully examined and help clinicians use appropriate symptom management and adjuvant strategies in this patient population.In advanced PC, tools such as the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), the EORTC Quality of Life Questionnaire Pancreatic Cancer Module (QLQ-PAN26), and the EuroQoL 5-Dimension Questionnaire (EQ-5D) have been used to assess the effect of therapy on QoL.To address this need, we conducted a systematic literature review  of studies evaluating QoL in patients with early-stage PC who underwent resection to (1) assess the landscape of the QoL PROMs used, (2) understand how QoL changes over time after surgical resection, and (3) assess which specific thresholds have been used to define a minimally important difference (MID) in QoL.ClinicalTrials.gov and International Clinical Trials Registry Platform) were searched through January 24, 2019. In addition, congress abstracts and presentations  from 2014 to 2017 were searched. Studies were included in accordance with the PRISMA statement.18 Search terms were designed to include specific populations (resectable or borderline-resectable PC), interventions (adjuvant or neoadjuvant chemotherapy), and outcomes . Any of the following study designs were permitted: randomized, controlled trials ; single-arm trials; observational studies; prospective studies; and protocols (for the MID and PROM identification objectives). Only studies published in English were considered. The original search did not identify any study reporting MID results for the EORTC QLQ-PAN26 PROM; therefore, a supplemental search with expanded search terms  was conducted to identify studies that assessed MID for EORTC QLQ-PAN26 . Studies of advanced PC, case series, case reports, nonsystematic literature reviews, nonhuman studies, and studies with no abstract were excluded. Duplicates were removed, and only the most up-to-date reports of research were included .A team composed of medical oncologists, health economics and outcomes research scientists, and a statistician formed a panel to develop the search, selection, and review strategies. Databases  and registries , interventions , and outcomes  were extracted from the included studies into a database.19 and randomized controlled trials were assessed using the Cochrane risk-of-bias tool.20 The NOS assesses study quality in 3 domains—selection, comparability, and outcome—and assigns scores of ≤4, 2, and 3 points, respectively, yielding a total maximum score of 9. A study was considered to be of high quality if the total NOS score was ≥7.22 The Cochrane risk-of-bias tool assesses study quality in 6 bias domains: selection , performance (blinding of participants and personnel), detection (blinding of outcome assessments), attrition (incomplete outcome data assessment), reporting (selective reporting), and other (any important concern not covered in the other domains). The Cochrane tool assigns a risk of bias—low, high, or unclear—for each category.The study quality was assessed independently by 2 reviewers, and a third reviewer resolved any disagreements. Nonrandomized observational studies were assessed using the Newcastle-Ottawa Scale (NOS),23 and assessed longitudinally when possible. The MID estimates for the most frequently used PROMs were assessed.In a narrative synthesis, the EORTC QLQ-C30 global health status (GHS)/QoL scale scores were compared with EORTC QLQ-C30 reference normsOf the 750 records identified initially, 660 were captured from the general search; the supplemental search produced 90 additional records Fig. . After r47 and the remaining 36 were full journal articles, including 3 study protocols.58 The studied populations included patients in North America, Europe, and Asia who typically received neoadjuvant and/or adjuvant chemotherapy and were assessed for QoL for a variable period .The key characteristics of the included studies and their respective populations are shown in Table Using NOS, 11 of the 28 observational studies were assigned a score of ≥7 , 13 received a score of 5 or 6 , and 4 received a score of 3 or 4 ; among all 39 studies included from the original and supplemental searches, 32 (82%) used EORTC QLQ-C30 and/or QLQ-PAN26  or the first postsurgical data (n = 5). The baseline EORTC QLQ-C30 GHS/QoL scores in early-stage PC  seemed similar to reference norms reported for PC  but lower than those reported for all cancers .Overall, 13 studies reported longitudinal QoL data; of these, 11 studies reported longitudinal EORTC QLQ-C30 GHS/QoL data (Table P < 0.01) and 2 months (P = 0.03) in postsurgical versus presurgical scores.55 In another study, the overall QoL scores were significantly lower in patients receiving chemotherapy (5-fluorouracil plus leucovorin [P = 0.03] or gemcitabine [P = 0.001]) versus observation at 3 months after surgery, but the scores were similar at 12 months after surgery . Most studies (7/10) reported no statistically significant change in GHS/QoL scores over the follow-up period , which showed no change in global health and overall QoL during 12 postoperative months in 6 of the 12 studies; the remaining 6 studies reported a postoperative decline in QoL that recovered after 3 to 6 months.62 Similar trends were seen in physical and social functioning domains and in pain, fatigue, and diarrhea symptoms scales.62 The initial decline in QoL is consistent with a delayed initiation of adjuvant chemotherapy in a considerable proportion of patients with resected PC,64 and the recovery and stability suggest that QoL may not be negatively affected by chemotherapy, at least in the longer term. Additional research is needed to understand the effect on QoL of other important factors, such as use of neoadjuvant chemotherapy and intensity of adjuvant chemotherapy.In this systematic literature review assessing QoL PROMs in early-stage PC, EORTC QLQ-C30 and QLQ-PAN26 were identified as the most commonly used QoL PROMs. The EORTC QLQ-C30 GHS/QoL scores at baseline were consistent with reference norms for PC but lower than those for all cancers collectively, supporting the high humanistic burden  and unmet need for these patients. The present systematic literature review is one of the few that comprehensively assessed longitudinal QoL data before and after pancreatic resection. The change in QoL over time after surgery varied across the 11 studies that reported these data, but the overarching observation was that QoL initially declined after surgery as observed previously,66 Two studies also used the same threshold for EORTC QLQ-PAN26 scales, but overall, the MID data for this PROM were limited. Two studies for EORTC QLQ-C30 and 1 for EORTC QLQ-PAN26 used 0.5 × baseline SD as a threshold for identifying clinically important change in QoL. For EORTC QLQ-C30, this threshold seems equivalent to a change of approximately 8 to 10 points in mean scores55; for EORTC QLQ-PAN26, this threshold may be slightly higher (approximately 10–15 points).55 A recent study underscored the unavailability of reference values for EORTC QLQ-PAN26 in the United States,45 further suggesting that MID has not been assessed comprehensively and that there is a need to fully establish the reference values for this PROM. The systematic literature review by van Dijk et al62 did not assess MID values.The MID for EORTC QLQ-C30 and QLQ-PAN26 may be useful in understanding the clinically relevant impact on QoL of treating early-stage PC. An MID of 10%  change in mean QLQ-C30 scores was considered to be clinically important in most studies. This was generally consistent with the previously reported mean differences between groups  or those over time .Both EORTC QLQ-C30 and QLQ-PAN26 seem to be useful PROMs in assessing QoL in early-stage PC. However, because EORTC QLQ-PAN26 is specifically designed to assess QoL in patients with PC, it may provide more relevant data to help physicians effectively manage symptoms and make treatment decisions in this patient population. Additional research is needed to further validate the EORTC QLQ-PAN26 PROM and establish the MID for adjuvant and neoadjuvant chemotherapy in early-stage PC.11; however, only approximately 50% of all patients undergoing pancreatic resection receive adjuvant therapy.64 Pancreatic resection is associated with significant postsurgical morbidity and impaired QoL,5 and postsurgical complications are associated with significantly lower rates and delayed administration of adjuvant therapy.64 Hence, there may be reluctance among physicians and patients toward adjuvant chemotherapy, which could prompt considerations of neoadjuvant or perioperative treatment. A recent study showed that patients with PC who were undergoing resection experienced high levels of depression before surgery through 6 months after surgery; the study suggested that managing physical symptoms and providing psychological support before surgery may improve QoL outcomes in these patients.67 Results from this systematic literature review may guide more efficient management of patients with early-stage PC who are receiving adjuvant chemotherapy and thus improve the overall outcomes in these patients.Understanding QoL in patients with early-stage PC may help improve management strategies after pancreatic resection. Adjuvant chemotherapy improves survival outcomes and is recommended by the National Comprehensive Cancer Network, ASCO, and ESMO guidelines as a standard of careThe studies included in this analysis were heterogeneous in terms of study design (populations and interventions [including the type of chemotherapy]) and QoL assessments . The reference norms with which the early-stage PC QoL outcomes from this study were compared are approximately a decade old and include all stages of cancer, but these types of data are generally limited in availability, and the norms used here are, to our knowledge, the only such currently available. As a result of disease recurrence, treatment withdrawal, or death, longitudinal QoL assessments do not include the entire initial patient population; therefore, improvement in QoL observed in some studies may reflect survivor selection bias. The changes in QoL over time are presented here in terms of statistical significance, which may not always align with changes of clinical significance. Some did not assess QoL before surgery, which makes it difficult to assess the extent of QoL recovery to the presurgical levels. To partially address this limitation, the graphs across studies were normalized to the time of surgery, which helped to standardize and clarify the trajectory of scores over time. The quality of included studies, as assessed by the NOS and Cochrane risk-of-bias tools, was generally low; however, their collective use in this analysis allowed for a comprehensive assessment of QoL to address an important question for early-stage PC.In conclusion, EORTC QLQ-C30 and QLQ-PAN26 are the most commonly used PROMs for assessing QoL in patients with early-stage PC who are undergoing surgery. The poor EORTC QLQ-C30 GHS/QoL scores in PC compared with scores in all cancers indicate a high unmet need in this patient population. Although the aforementioned limitations, especially survival bias, should be considered, QoL declined immediately after surgery, recovered in approximately 3 to 6 months, and remained generally stable for the rest of the follow-up period. The MID values for QLQ-C30 may help elucidate the clinically relevant impact on QoL of treating early-stage PC. Future research should establish the MID for EORTC QLQ-PAN26 in this patient population.The results of this and other studies reveal QoL patterns in patients with early-stage PC who underwent surgical resection. With this knowledge, physicians might be able to identify points of intervention through several approaches: symptom(s) management, psychological and social support, neoadjuvant therapy, and adjuvant therapy initiation as early as possible depending on the individual patient situation and opinion of the treating physician. Collectively, a holistic approach to QoL management may help further refine the treatment guidelines in this patient population.


Background: Although studies assessing cardiovascular comorbidities and myocardial injury in Coronavirus disease 2019 (COVID-19) patients have been published, no reports focused on clinical outcomes of myocardial injury in patients with and without chronic coronary syndromes (CCS) are currently available. Methods: In this study, consecutive COVID-19 patients admitted to four different institutions were screened for enrolment. Patients were divided into two groups (CCS vs. no-CCS). Association with in-hospital mortality and related predictors represented the main study outcome; myocardial injury and its predictors were deemed secondary outcomes. Results: A total of 674 COVID-19 patients were enrolled, 112 (16.6%) with an established history of CCS. Myocardial injury occurred in 43.8% patients with CCS vs. 14.4% patients without CCS, as confirmed by high-sensitivity cardiac troponin (hs-cTn) elevation on admission or during hospitalization. The mortality rate in the CCS cohort was nearly three-fold higher. After adjusting for disease severity, myocardial injury resulted significantly associated with in-hospital mortality in the no-CCS group but not in CCS patients. Conclusions: Patients with CCS and COVID-19 showed high mortality rate. Myocardial injury may be a bystander in CCS patients and COVID-19, while in patients without known history of CCS, myocardial injury has a significant role in predicting poor outcomes. In recent times, the available body of evidence assessing the novel Coronavirus disease COVID-19) has led to a progressive steering from a lung-centered disease paradigm in favor of a systemic disease concept. Several studies have reported the presence of an important interplay between the cardiovascular system, coagulation derangements, and COVID-19 9 has led,3,4. TheIt is well accepted that respiratory infections—e.g., influenza A/B and previous severe acute respiratory syndrome (SARS) infections—are associated with CV events, cardiac arrhythmias , and espPatients with chronic coronary syndromes (CCS) defined according to the European guidelines  may be mThe aim of this study was to evaluate clinical outcomes of CCS patients with COVID-19 and the potential mechanisms of myocardial injury in CCS and no-CCS patients with COVID-19.Consecutive confirmed cases of COVID-19 admitted to four Italian institutions  between 23 February 2020 and 1 May 2020 were screened for enrolment. Patients were prospectively enrolled, and data were retrospectively analyzed. A confirmed case of COVID-19 was defined by a positive result on a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay performed on a nasopharyngeal swab, according to the World Health Organization (WHO) guidelines.Patients with CCS were defined as specifically stated by the European Guidelines , as follPatients presented to the emergency department (ED) with SARS-CoV-2 infection and ACS were excluded from the analysis. Clinical outcomes were monitored up to the final date of follow-up (11 May 2020). All patients still hospitalized or with an incomplete follow-up were excluded.This study was approved by the local ethical board (project identification code 2020/ST/081) in accordance with national regulations and was conducted in accordance to the Declaration of Helsinki. The cause of death in all patients were adjudicated in a standardized fashion.2, obtained with the CKD-EPI equation. Baseline laboratory values were analyzed on arterial and venous blood samples collected at the time of hospitalization. Radiological findings were assessed using a chest radiograph severity scoring system validated in patients with severe acute respiratory infection  (IQR) if normally or nonnormally distributed, respectively. Comparisons were performed using a student T test, a Mann Whitney U test, a Chi Square test, or a Fisher exact test, as appropriate. A multivariate logistic regression was performed to test the association between dichotomic outcomes  and cardiovascular risk factors and/or parameters of clinical interest for COVID-19 patients; strength of association is reported using odds ratios (OR). A by-group survival analysis was performed using Kaplan–Meier curves. Kaplan–Meier curves were compared first using a log-rank test for overall difference among the three groups, and then a post hoc all pair-wise comparisons was performed using a Bonferroni correction. A two-tailed A total of 674 consecutive COVID-19 patients were prospectively enrolled, 112 (16.6%) of whom had an established history of CCS. CCS patients were significantly older than no-CCS patients and presented with more CV risk factors. Both CV  and non-CV (chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)) comorbidities were more frequent in the CCS group. Patients with CCS were more likely to receive CV medications. Baseline characteristics of the whole cohort are summarized in Clinical characteristics on admission are summarized in 2) and PaO2/FiO2 ratio were significantly lower among CCS patients. Patients with CCS had more severe findings on admission chest x-ray.CCS patients were less likely to present to the ED with fever, cough, and sore throat, although no difference in the time interval between symptom onset and admission was found. Oxygen saturation (SaOp < 0.001), as confirmed by elevation of hs-cTn at admission or during hospitalization. The mortality rate in the CCS cohort was nearly three-fold higher.Median in-hospital stay, intensive care unit (ICU) admissions, and use of mechanical invasive ventilation were similar in the two groups. When compared to non-CCS patients, CCS patients received noninvasive ventilation (NIV) more frequently and developed ARDS more often. Myocardial injury occurred in 43.8% patients with CCS vs. 14.4% patients without CCS  or coronary artery bypass graft (CABG) showed a trend towards significance for a higher risk of death. A stratification of in-hospital mortality between CCS and non-CCS was performed and is reported in p = 0.171). A second multivariate analysis exploring predictors of myocardial injury is reported in Both CCS and no-CCS patients with myocardial injury had a higher mortality than no-CCS patients (both < 0.001), while no difference between groups was found , in line with a smaller cohort of patients with CV diseases described by Inciardi et al.  (36%). NObviously, patients with CCS have significantly more underlying CV risk factors and more comorbidities. Several studies have shown an association between chronic CV diseases and the development of severe complications associated with COVID-19 (including ARDS and death) ,21,24 anOn admission, CCS patients presented with higher creatinine and lower hemoglobin, which seem to be an expression of underlining CKD and anemia, more than multiorgan involvement due to COVID-19 severity. CCS patients were treated with similar drug regimens . The increased mortality observed in CCS patients occurred despite a more frequent use of tocilizumab, which indeed has not shown significant impact on the clinical outcomes in another study , and hepMyocardial injury has been shown to be a common condition among COVID-19 hospitalized patients and has been associated with higher risk of in-hospital mortality in general populations ,3,5,7,33At multivariate analysis A, myocarAdditionally, an inflammatory state may trigger production of cytokines that can activate inflammatory cells in atherosclerotic plaques . Thus, iIn patients with a preexisting CCS, myocardial injury may be due predominantly to a worsening of the preexisting CCS condition due to an increased mismatch of the supply/delivery of oxygen, while in patients without a preexisting diagnosis of CCS, a direct myocardial damage (myocarditis-like) may have a relevant role. However, at present, there are no findings providing evidence of direct infection and replication of SARS-CoV-2 in cardiomyocytes .When evaluating myocardial injury, it should be remembered that low levels of hs-cTn (slightly above the URL) can be detected in many CCS patients ,36 and tn = 26). On the other hand, patients with elevated hs-cTn but without preexisting CCS have less confounders that may lead to myocardial injury, and therefore, it is more likely that hs-cTn elevation represents a new-onset myocardial involvement which can significantly worsen prognosis and clinical outcomes. Myocardial injury in no-CCS patients may be more easily detected by hs-cTn elevation in contrast to what happens in CCS patients, in whom hs-cTn elevation is more likely a nonspecific finding.Second, a trend towards significance shown in non-revascularized patients may support our findings, since patients with moderate stenoses not suitable for revascularization or who had stable CCS treated with medications, may be more susceptible to mismatch between oxygen supply or demand and therefore may have a higher risk of death  values were not available in the majority of patients and are not reported in our analysis. Moreover, due to the logistic limitations of managing patients in isolation, electrocardiograms (ECGs) and echocardiograms as well as arrhythmic data that were not routinely collected with ECG continuous monitoring were acquired in a few patients only.Patients with CCS and COVID-19 have a poor prognosis and a high mortality rate that was nearly three-fold higher than that observed in those without a known history of CCS. Although myocardial injury has been shown to be associated with worse outcomes in COVID-19, hs-cTn elevation had a prognostic value in non-CCS patients, while it was not predictive of poor outcomes in patients with CCS. Myocardial injury may be a bystander in CCS, whereas in patients without known history of CCS, it has a significant role in predicting poor outcomes. Further data are needed to understand proper mechanisms of myocardial injury in CCS and no-CCS patients with COVID-19.


Pirfenidone and nintedanib are antifibrotic therapies which slow disease progression in idiopathic pulmonary fibrosis (IPF), an irreversible, progressive lung disease with poor prognosis. We compared adherence, persistence, and healthcare costs between patients initiating one of the two therapies.We used the IBM Watson Health Commercial and Medicare Supplemental claims databases to select patients with IPF with ≥1 pharmacy claim for pirfenidone or nintedanib between 10/1/2014 and 6/30/2018. Adherence (proportion of days covered ≥0.80) and persistence (time to a gap of ≥60 days without medication or switch to the other antifibrotic medication) based on the days’ supply and service date fields on claims were measured over a variable-length follow-up period. Healthcare costs, all-cause and respiratory-related, were measured over the persistent period and a fixed 12-month follow-up period. Inverse probability of treatment weights were applied to models comparing adherence, persistence, and costs between the two cohorts.p = 0.513). The proportions of patients who discontinued/switched were also similar (pirfenidone = 41% vs. nintedanib 43%); however, in a weighted model, the hazards of discontinuation/switching was lower for the pirfenidone cohort . While patients were persistent on therapy, weighted all-cause healthcare costs were comparable , but weighted respiratory-related costs were significantly lower for the pirfenidone cohort . Weighted annual total all-cause and respiratory-related healthcare costs were comparable between cohorts over the fixed 12-month follow-up period, but the pirfenidone cohort had significantly lower weighted annual mean antifibrotic drug costs than the nintedanib cohort .Overall, 799 pirfenidone patients and 656 nintedanib patients were identified. Similar proportions of patients were adherent in both cohorts (pirfenidone = 49% vs. nintedanib = 51%) and there was no significant difference in the odds of being adherent after weighting (odds ratio = 1.1, Pirfenidone use was associated with longer time to discontinuation/switch, lower antifibrotic drug costs, and lower respiratory-related total costs compared to nintedanib use. Idiopathic pulmonary fibrosis (IPF) is an irreversible, progressive, fibrotic lung disease, in which the lung tissue becomes thick and scarred, reducing oxygenation of the blood and resulting in end organ damage , 2. In tIn 2014, the US Food and Drug Administration approved the first two antifibrotic therapies for IPF pirfenidone and nintedanib , 10. In Analyses of data on US Medicare beneficiaries have estimated that the annual cost of IPF to the US healthcare system, excluding medication costs, is $2 billion . In partThis observational retrospective cohort analysis utilized de-identified US administrative claims data covering October 1, 2014, to June 30, 2018, from three IBM MarketScan Databases: the Commercial Claims and Encounters , the Medicare Supplemental and Coordination of Benefits (Medicare), and the Early View Databases . The comThe Early View database includes the same components as the Commercial and Medicare databases for the period of October 1, 2017, through June 30, 2018. Claims are available in the Early View database within 45 days of the end of the service month, and previous analysis has shown that over 97% of drug claims are fully adjudicated within the 30 days of the service date making it appropriate to use for treatment pattern analysis but not for HRU and cost analyses.Study variables were based on enrollment information, International Classification of Diseases, 9th and 10th Revision, Clinical Modification (ICD-9-CM and ICD-10-CM) codes, Current Procedural Terminology 4th edition codes, Healthcare Common Procedure Coding System codes, and National Drug Codes. All study data were accessed with protocols compliant with US patient confidentiality requirements, including the Health Insurance Portability and Accountability Act of 1996 regulations (HIPAA). The databases used in the study are fully de-identified and compliant with the HIPAA. Research using the MarketScan Research Databases falls under Title 45 of the Code of Federal Regulations Part 46.101(b)(4) exemption from Institutional Review Board review because the databases contain only information that cannot be used to identify study subjects. As the data were de-identified, consent from patients was not sought.The study population consisted of patients with at least one outpatient pharmacy claim for pirfenidone or nintedanib from October 1, 2014, to June 30, 2018. The first such claim during the study period was set as the index date. Patients were required to be at least 40 years old on the index date, have continuous enrollment with medical and prescription coverage for at least 12 months before the index date (baseline period), and have at least one non-diagnostic inpatient or outpatient claim with an diagnosis code for IPF  between the baseline period and June 30, 2018. Patients were excluded if they had evidence of other interstitial lung diseases  between the index date and June 30, 2018.Three datasets were constructed from the set of patients who met the above criteria: the treatment patterns dataset, the variable-length HRU and cost while persistent dataset, and the 12-month fixed-length HRU and cost dataset. Patients in each dataset were stratified into two cohorts based on the antifibrotic received on the index date: pirfenidone or nintedanib.The treatment patterns dataset contained all eligible patients and followed them from 12 months before their index date until the earliest of the following: inpatient death, end of continuous enrollment, or June 30, 2018 (end of the Early View data). The variable-length HRU and cost while persistent dataset comprised patients who had an index date on or before September 30, 2017 (end of non-Early View data). Patients were followed from 12 months before their index date until the earliest of the following: inpatient death, end of continuous enrollment, treatment discontinuation (defined below), or September 30, 2017. The 12-month fixed-length HRU and cost dataset comprised patients who had an index date on or before September 30, 2016 and at least 12 months of continuous enrollment in non-Early View data. Patients were followed from 12 months before their index date through 12 months after their index date, regardless of the length of time they persisted on their index medication.Demographic characteristics, including age, sex, and geographic region, were measured on the index date. Baseline clinical characteristics were measured during the baseline period and included: the Deyo-Charlson Comorbidity Index (CCI) , the CCITreatment adherence, discontinuation, persistence, switching, and re-initiation were assessed during the variable follow-up period for all patients in the treatment patterns dataset. Medication adherence was measured by the proportion of days covered (PDC) defined as the sum of days’ supply during the follow-up period divided by the length of the follow-up. To account for titration, an additional 7 days were added to the days’ supply of the first pirfenidone prescription claim unless the supply was 207 pills for 30 days, which would be correct if following the recommended titration schedule. Overlapping days’ supply between consecutive fills were appended, and the maximum PDC was truncated at a value of 1.0. Patients with a PDC greater than 0.8 were considered adherent.Discontinuation was defined as having a gap in treatment of ≥60 days. The date of the last day supply before the first 60-day gap was the discontinuation date. Patients who had a lung transplant before the end of a 60-day gap in treatment were not considered to have discontinued. Switching was defined as a filled prescription for the alternate antifibrotic medication. The date of the new prescription was defined as the switching date. The persistence period was defined as the time from the index date to the earliest of the following: discontinuation, lung transplantation, switching, or end of follow-up. Re-initiation was defined as having a new claim for the index drug after discontinuation.HRU and cost outcomes were: inpatient admissions (excluding lung transplants), outpatient services (including emergency department visits and physician office visits), and outpatient pharmacy claims. Because of variable follow-up, per-patient per-month (PPPM) all-cause, respiratory-related, and index drug-related HRU and costs were recorded for the period of persistence on index medication for all patients in the variable-length HRU and cost dataset. Per-patient per-year  all-cause, respiratory-related, and index drug-related HRU and costs were recorded for the 12-month post-index period for all patients in the fixed-length HRU and cost dataset. All-cause utilization included all claims, regardless of diagnosis, procedure, or medication. Respiratory-related utilization included inpatient claims with a primary diagnosis of respiratory disease, outpatient claims with a diagnosis of a respiratory disease in the first position and pharmacy claims for respiratory therapies .Costs were the paid amounts of fully adjudicated claims, including insurer and health plan payments, as well as patient cost-sharing in the form of copayment, deductible, and coinsurance. All-cause costs include the costs on all claims; while respiratory-related costs include the cost of claims determined to be respiratory-related as defined above. All costs were inflated to 2017 US dollars using the medical care component of the Consumer Price Index .t-tests.Frequencies and percentages were reported for categorical variables, and statistical significance between treatment groups was determined using Chi-square tests. Mean and standard deviation (SD) were reported for continuous variables, and statistical significance between treatment groups was determined using two-sample Inverse probability of treatment weighting (IPTW) was used to address cohort imbalances via a logistic regression model, treating pirfenidone vs. nintedanib as the dependent variable. Covariates included age group , sex, geographic region of residence, CCI without COPD codes, evidence of COPD, evidence of stroke, evidence of recent pneumonia, and baseline visit to an ILD Center of Excellence. Cohort balances were evaluated by standardized mean difference where a value of less than or equal to 0.1 indicates a good balance  and hazard ratios (HR) were reported with 95% confidence intervals (CI). Predicted costs were estimated for each group using the recycled prediction method and bootstrap resampling to estimate 95% CI. The alpha level for all statistical tests was 0.05.Statistical analyses were conducted using SAS 9.4 and R.P = 0.027).Overall, 1455 patients with IPF met the selection criteria . Descriptively, the mean (SD) PDC in all patients and in both treatment groups was 0.66 (0.35) (Table P = 0.532).The mean length of follow-up data available for treatment pattern analysis was 480.2 days (median: 403 days) among pirfenidone-treated patients and 446.6 days (median: 383 days) among nintedanib-treated patients (P = 0.010) (Table P = 0.338). Among those with discontinued, 17.8% of patients re-initiated pirfenidone, and 14.0% re-initiated nintedanib (P = 0.197). The mean (SD) time to re-initiation of index medication was not significantly different between pirfenidone-treated and nintedanib-treated patients . Among the 10.8% of pirfenidone patients and 8.8% of nintedanib patients who switched to the alternate antifibrotic, the time between the index and switching date was shorter for pirfenidone patients .The mean (SD) duration of persistence with index medication was significantly longer in the pirfenidone vs. nintedanib cohort in an comparison unadjusted for differences in patient characteristics . However, indexing on pirfenidone was associated with a longer time to discontinuation or switching than indexing on nintedanib  .In models weighted to account for differences in baseline characteristics, no significant difference in odds of adherence (OR [95% CI]) was observed between patients treated with pirfenidone and patients treated with nintedanib . While persistent with antifibrotic therapy, a significantly greater proportion of patients treated with pirfenidone than patients treated with nintedanib had at least one all-cause inpatient hospitalization  or respiratory-related inpatient hospitalization  (Table P = 0.208) and respiratory-related inpatient hospitalizations  during the persistent period were not statistically significant.Among the 697 pirfenidone users and 551 nintedanib users who indexed before September 30, 2017, the mean length of follow-up while persistent was 260.7 days  in the pirfenidone cohort and 229.6 days  in the nintedanib cohort (P = 0.115), but predicted respiratory-related costs were significantly lower in patients treated with pirfenidone than patients treated with nintedanib  .While patients were persistent with therapy, the predicted all-cause healthcare costs based on the weighted multivariable models were comparable between pirfenidone and nintedanib treated patients  Fig. . While pP = 0.629). While there was no statistically significant difference in the proportions of patients with at least one respiratory-related inpatient hospitalization, the mean (SD) length of stay for respiratory-related hospitalizations was significantly shorter in patients treated with pirfenidone than patients treated with nintedanib .Among the 348 pirfenidone users and 266 nintedanib users with at least 12 months of post-index non-Early View data, 12-month all-cause and respiratory-related healthcare utilization rates were generally similar between cohorts (Table P = 0.007).In multivariable models, the annual total all-cause and respiratory-related healthcare costs among the subset of patients with 12 months of post-index enrollment were comparable between patients treated with pirfenidone and patients treated with nintedanib Fig. . HoweverIn a real-world setting, patients with IPF who were treated with pirfenidone had a longer time to discontinuation or switching and similar odds of adherence compared to patients treated with nintedanib. While persistent on index medication, patients treated with pirfenidone had 15% lower index drug costs, 11% lower respiratory-related costs, and similar all-cause costs than patients treated with nintedanib. This was in spite of higher utilization of all-cause and respiratory-related inpatient services while they were persistent on their index medication. Among the subset of patients with 12 months of follow-up data, all-cause and respiratory-related adjusted annual costs were similar regardless of index medication; however, index drug-related costs were lower for patients who indexed on pirfenidone.Adherence to and persistence with antifibrotic therapies in IPF are important for maintaining treatment benefits and slowing lung function decline; however, there is limited existing data on treatment patterns as pirfenidone and nintedanib have only been recently approved to treat IPF in the US –27. Two To our knowledge, no analyses comparing healthcare costs between IPF patients treated with pirfenidone and IPF patients treated with nintedanib have been published. Prior to the approval of pirfenidone and nintedanib, analyses of Medicare and commercially insured patients with IPF have estimated mean annual healthcare costs ranging from $26,000 to $ 59,000 and mean annual medical costs  ranging from $20,000 to $52,000 , 20, 28.A previous analysis has shown that acute exacerbations in the first 6 months after diagnosis of IPF and a greater decline in forced vital capacity are associated with increased healthcare utilization and shorter overall survival . In studThere are several limitations that should be considered when interpreting the findings of this study. First, as with any analysis of healthcare claims data, the adherence and persistence results reflect patterns in prescription fills (and not necessarily use) of the index medications; therefore, they may not fully capture usage patterns of antifibrotic therapy among patients with IPF. Second, unadjusted results for healthcare utilization did not account for potential differences in patient characteristics between treatment groups. Third, cost comparisons were adjusted for some potential confounders; however, residual confounding may exist due to the lack of clinical data included in administrative claims data or other unobserved differences between cohorts. Because patients were selected based on initiation of pirfenidone vs. nintedanib and clinical notes are not available, we were not able to control for years since initial diagnosis. Measures of disease severity, such as results of pulmonary function tests and GAP stage, were also not available. Fourth, only a small number of patients had 12 months of non-Early View follow-up data, so the analysis may be underpowered to detect differences in HRU and costs. Fifth, the proportions of patients with specific utilization types measured during the persistent period did not account for variable follow-up time. Sixth, prior to the approval of these medications there was no effective treatment for IPF; therefore, patients in this analysis may be sicker on average than future patients who have access to these medications upon initial diagnosis. Patients who did not survive 12 months after index medication initiation did not meet the continuous enrollment criteria for the fixed 12-month follow-up outcomes. Finally, analysis was restricted to patients with commercial or Medicare Supplemental insurance and findings may not extend to patients with other types of insurance or no insurance.After controlling for patient differences, IPF patients on pirfenidone remained on index therapy significantly longer than nintedanib patients. While patients were persistent on their index medication, weighted index drug costs and respiratory-related total costs were significantly lower among patients treated with pirfenidone compared to nintedanib patients.Additional file 1. Demographic and clinical characteristics before and after weighting for patients with index date prior to 10/1/2017.


Inter-facility transfer is an important strategy for improving access to specialized health services, but transfers are complicated by over-triage, under-triage, travel burdens, and costs. The purpose of this study is to describe ED-based inter-facility transfer practices within the Veterans Health Administration (VHA) and to estimate the proportion of potentially avoidable transfers.This observational cohort study included all patients treated in VHA EDs between 2012 and 2014 who were transferred to another VHA hospital. Potentially avoidable transfers were defined as patients who were either discharged from the receiving ED or admitted to the receiving hospital for ≤1 day without having an invasive procedure performed. We conducted facility- and diagnosis-level analyses to identify subgroups of patients for whom potentially avoidable transfers had increased prevalence.p < 0.001), and 22.8% of all VHA-to-VHA transfers were potentially avoidable transfers. The 3 disease categories most commonly associated with inter-facility transfer were mental health (34%), cardiac (12%), and digestive diagnoses (9%).Of 6,173,189 ED visits during the 3-year study period, 18,852 (0.3%) were transferred from one VHA ED to another VHA facility. Rural residents were transferred three times as often as urban residents (0.6% vs. 0.2%, VHA inter-facility transfer is commonly performed for mental health and cardiac evaluation, particularly for patients in rural settings. The proportion that are potentially avoidable is small. Future work should focus on improving capabilities to provide specialty evaluation locally for these conditions, possibly using telehealth solutions. Over 2.4 million Veterans seek care from Veterans Health Administration (VHA) emergency departments (EDs) each year, and 40% of these Veterans live in rural America . ProvidiIn many low-volume EDs, inter-facility transfer is used as a strategy for moving patients rapidly to hospitals equipped to care for them , 12. WelThe VHA provides critical emergency and specialty care to rural Veterans. All Veterans who present for care are evaluated and have standard diagnostic tests performed, but some that present to smaller facilities require transfer to larger facilities for diagnostic or therapeutic procedures or for availability of inpatient services. While inter-facility transfer provides access to care that would otherwise be unavailable in rural communities, it also imposes a substantial hardship for rural Veterans and their families by displacing them and increasing costs of care. Inter-facility emergency transfers often occur when Veterans are most vulnerable due to their acute illness, and complex care coordination can contribute to delays and triage mismatch , 19.The objective of this study was to describe ED-based transfer patterns within in the VHA system, with a focus on potentially avoidable transfers (PAT). This analysis is the first step in developing targeted interventions such as ED-based telehealth to decrease the number of avoidable transfers and improve efficiency of inter-facility transfer within the VHA. To accomplish that objective, our goals were to (1) describe the VHA-to-VHA transfer population, (2) identify patient and health system factors associated with PAT, and (3) define geographic “hot spots” of high volumes of potentially avoidable transfer as a first step toward developing regional interventions. Our hypothesis was that geographic and diagnostic categories exist that are related to PATs, and that these transfers would disproportionately rural Veterans in smaller EDs on nights and weekends.International Classification of Diseases, 10th edition (ICD-10) in 2015. Data were abstracted from the VHA Clinical Data Warehouse (CDW), which contains national data from clinical and administrative data systems collating patient-level, visit-level, provider-level, and institution-level information. This project was determined not to be human subjects research by the local Institutional Review Board , and this study is reported in accordance with the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) statement ), cardiac , and digestive  conditions, with these top 3 categories comprising 55% of all transfers. The top ICD-9 diagnosis related to VHA ED transfer was suicidal ideation (V62.84). Among patients transferred for a procedure, interventional cardiac procedures were most common, constituting 45% of all procedures  and cardiac  diseases , but smaller EDs did not have a higher prevalence of PAT . That finding suggests that while smaller hospitals transfer a greater proportion of patients, ED size was not associated with transfer appropriateness. Hospitals staffed by at least 50% board-certified emergency physicians had a lower proportion of VHA transfers than those that did not , but the proportion of PAT was higher in hospitals with more than 50% board-certified emergency physicians . Patients were more likely to be transferred from hospitals that did not accept incoming unscheduled ambulance traffic  into the ED . For interpretation of computed tomography (CT) studies, transferring hospitals were more likely to use tele-radiology between 8 am and 5 pm Monday-Friday (8% vs. 4%) and were less likely to have radiology residents interpreting studies on nights and weekends (10% vs. 21%), which is a proxy for the staffing and availability of specialized services at these facilities.Transferred Veterans were more commonly transferred from smaller index VHA EDs , but they were equally likely to follow up at the index hospital compared with those who were not transferred (79% vs. 79%).In summarizing data from the HAIG survey, 48% of medical directors of VHA EDs cited the transfer process as overly burdensome, with 29% identifying difficulties with identifying an accepting physician/facility, 13% identifying challenges with obtaining approval for transfer, and over 65% noting that administrative processes contribute to delay in transfer.Variation in transfer proportions across index hospitals was high, ranging from 0 to 6% of total patients presenting to the ED who were transferred. PAT also varied widely, and PAT was not related to total transfer volume. Many high-transfer hospitals have an accompanying hospital that accepts the majority of transfers, but some sites have multiple transfer destinations Fig. . There wAlthough mental health-related transfers were the most prevalent condition for which VHA-to-VHA transfer was performed, in Veteran Integrated Service Network (VISN) numbers 7  and 17 (Texas), mental health transfers comprise over 60% of total inter-facility transfers. Similarly, circulatory system conditions comprise over 20% of total transfers VISN 1 , 6 (North Carolina and Virginia), and 15 . Figure Adjusting for factors associated with inter-facility transfer, ED arrival at the index hospital on nights and weekends aOR 1.252) and hospitals with more than 50% board-certified emergency physicians (aOR 1.266) both were associated with increased probability of PAT, while rural patients were at lower risk (aOR 0.798). The diagnostic categories associated with the highest adjusted risk were nervous system diseases (aOR 1.617), musculoskeletal conditions (aOR 1.571), and injury and poisoning (aOR 1.374). Importantly, however, the groups at highest risk did not constitute the greatest absolute number of PATs (Table 52 and hop < 0.001). Characteristics of the subset of patients transferred for mental health are summarized in Additional file Because of the high prevalence of mental health-related transfers, we conducted a post hoc subgroup analysis to identify factors associated with PAT within this group. The strongest risk factor for PAT (compared with both appropriate transfer and non-transfer) was being treated at night or on the weekend  robust mental health resources available within the VHA and (2) limited local bed availability or high inpatient occupancy necessitating transfer for inpatient hospitalization. Compared with civilian hospitals, VHA facilities have fewer patients transferred with myocardial infarction, stroke, and traumatic injury .The overall goal of this project was to identify populations within the VHA where unnecessary transfers could be avoided. From our data, mental health diagnoses represent a rich target population for which telehealth might offer a plausible solution. Importantly, we feel that targeting mental health transfers is important because of the size of the population, despite the fact that the raw risk of PAT among that population is not elevated. Mental health providers are in critical shortage in most of the US , 41, andWhile myocardial infarction, stroke, and digestive conditions represented many transfers and many could be potentially avoidable, these conditions also commonly require procedural capabilities, and the need for those procedures may not be immediately obvious. Future work could develop additional interventions to better target inter-facility transfer in the group of patients needing cardiac catheterization, stroke care, or endoscopy, but these populations remain relatively small. Future work could also partner with local EMS services to better guide prehospital diversion practices. Despite the enriched mental health transfer population within VHA facilities, patients with mental health emergencies may benefit from provider-to-provider telemedicine in civilian hospitals as well, because factors driving inter-facility transfer and barriers to mental health access are ubiquitous outside the VHA.A final important observation from this study surrounds the results from the HAIG survey of ED medical directors. Nearly half of medical directors of VHA EDs cited the transfer process as overly burdensome, and the majority noted that administrative processes resulted in transfer delays. While inter-facility transfer is complex, efforts to reduce the administrative burdens could be one effective way for patients to reach definitive care more quickly and reduce boarding in VHA EDs. In this study, we did not examine timeliness of transfer or the prevalence or impact transfer boarding has on VHA EDs, but the volume of transfers suggests that future work should examine the impact of these relationships in more detail.Our study has several limitations. While administrative data provides a large sample, it limits the information available for individual patients to those coded in administrative claims. The second limitation is our definition of a transfer. The advantage of using the linkage method of identifying transfers is that we have high confidence that patients actually ended up receiving care in the receiving hospital. There could be some patients, however, who were discharged from the ED and presented to a different ED that we have inappropriately classified as transfer. Third, many patients were transferred from VHA EDs to non-VHA hospitals. While we were unable to assess PAT in non-VHA transfers, this remains an important population for future study. It also may be a population for which the motivations and outcome of interhospital transfer may differ from VHA transfers. Finally, our narrowly defined definition of PAT is not equivalent to avoidable transfer and some PAT may have still been necessary. Inter-facility transfer is a complex decision that would require more detailed qualitative patient-level analysis to better characterize specific reasons driving clinical decision-making.In conclusion, inter-facility transfer occurs in 0.8% of VHA ED visits, and only one-quarter of these VHA-to-VHA transfers are potentially avoidable. Rural Veterans are at high risk of VHA-to-VHA inter-facility transfer, but these transfers are no more likely to be PAT than for urban Veterans. Patients within VHA EDs are commonly transferred for mental illness, cardiac diseases, and digestive diseases, and there is wide variability between regions and hospitals in their transfer practices. Future work will focus on better understanding the reasons for transfers and factors that influence transfer decision-making, and future interventions will seek to improve the appropriateness, communication, and administrative factors surrounding inter-facility transfer.Additional file 1. Data dictionary for variables included in analysis.Additional file 2: Table S1. Most common procedures performed after VHA-to-VHA inter-facility ED transfer.Additional file 3: Table S2. Patient and hospital-level factors associated with VHA-to-VHA ED inter-facility transfer for mental health patients, 2012–2014.


These adverse effects were even more pronounced in the case where cutoffs were increased to either 72 h or 96 h. Independent risk factors for a delay in spinal surgery were a higher ISS (p = 0.036), a thoracic spine injury (p = 0.001), an AOSpine A-type spinal injury (p = 0.048), and an intact neurological status (p < 0.001). In multiple-injured patients with AOSpine A-type spinal injuries, an increased time to spinal surgery was only an independent risk factor for an increased LOS; however, in multiple-injured patients with B-/C-type spinal injuries, an increased time to spinal surgery was an independent risk factor for increased iLOS, LOS, and the development of sepsis. Conclusion: Our data support the concept of early spinal stabilization in multiple-injured patients with AOSpine B-/C-type injuries, especially of the thoracic spine. However, in multiple-injured patients with AOSpine A-type injuries, the beneficial impact of early spinal stabilization has been overemphasized in former studies, and the benefit should be weighed out against the risk of patients’ deterioration during early spinal stabilization.Background: Thoracolumbar spine fractures in multiple-injured patients are a common injury pattern. The appropriate timing for the surgical stabilization of vertebral fractures is still controversial. The purpose of this study was to analyse the impact of the timing of spinal surgery in multiple-injured patients both in general and in respect to spinal injury severity. Methods: A retrospective analysis of multiple-injured patients with an associated spinal trauma within the thoracic or lumbar spine (injury severity score (ISS) >16, age >16 years) was performed from January 2012 to December 2016 in two Level I trauma centres. Demographic data, circumstances of the accident, and ISS, as well as time to spinal surgery were documented. The evaluated outcome parameters were length of stay in the intensive care unit (ICU) (iLOS) and length of stay (LOS) in the hospital, duration of mechanical ventilation, onset of sepsis, and multiple organ dysfunction syndrome (MODS), as well as mortality. Statistical analysis was performed using SPSS. Results: A total of 113 multiple-injured patients with spinal stabilization and a complete dataset were included in the study. Of these, 71 multiple-injured patients (63%) presented with an AOSpine A-type spinal injury, whereas 42 (37%) had an AOSpine B-/C-type spinal injury. Forty-nine multiple-injured patients (43.4%) were surgically treated for their spinal injury within 24 h after trauma, and showed a significantly reduced length of stay in the ICU (7.31 vs. 14.56 days;  The patient with multiple injuries is a unique challenge for the trauma care team, even more so in association with spinal fractures. Traumatic spinal injuries in multiple-injured patients are less common in comparison to extremity injuries but present with an increasing incidence over the last decades ,2. Most Controversy still arises concerning the optimal timing for spinal surgery in the multiple-injured patient. In the literature, the discussion has ultimately focused on the question of early versus late surgical treatment and its consequences on mortality and the patients’ outcome ,7. RecenFor this reason, the aim of the present study is to analyse the impact of the timing of spinal surgery in multiple-injured patients both in general and in respect to spinal injury severity.This retrospective two-centre study was conducted on all multiple-injured patients with spinal injuries who were admitted to one of the two level I trauma hospitals between January 2012 and December 2016. Patients were eligible for further analysis if they met the following inclusion criteria: age >16 years; injury severity score (ISS) >16; associated spinal injury within the thoracic or lumbar spine; and a fully available computed tomography scan for spinal injury classification, according to the established AOSpine Classification . Demograp < 0.05 for all statistical tests. A power analysis was carried out with G * Power  and resulted in the following statistical power for each statistical test: 0.998 for the ANOVA, 0.963 for the t-test, and 0.999 for both the correlation analysis and the regression analysis.Data were collected from the inhouse clinical documentation system. Counts and frequencies were used to describe the sample. Correlation analysis (Spearman) was used to determine any dependence between the variables. For evaluation of influencing factors on the timing of surgery, a chi-square test and a one-way ANOVA was performed. Fisher’s exact test was used for categorical variables. Multivariable logistic regression analysis was performed using time to surgery, LOS, iLOS, and sepsis as dependent variables. Results are presented as odds ratios (ORs) with 95% confidence intervals. Significance was set at All testing procedures were performed exploratively, so no adjustment for multiple testing has been made. Statistical analyses were performed with IBM SPSS software . The study complies with the principles of the Declaration of Helsinki (2013) and was approved by the local ethical committee (#EK056/17).n = 102, 41%), followed by car accident  and motorcycle accident . In 153 patients (61%) the lumbar spine and in 97 patients (38%) the thoracic spine was involved. In 127 patients (51%) spinal stabilization was performed, of whom 14 patients had to be excluded due to missing data  were classified as AOSpine A-type injuries, whereas 42 fractures (37%) were classified as AOSpine B-/C-type injuries . SeventeTime to spinal surgery for the 113 multiple-injured patients included in the study is presented in p < 0.001) as compared to those were operated on later than 24 h while having a comparable overall injury severity . Furthermore, the length of hospital stay was significantly reduced by 10 days . The prevalence of sepsis was significantly higher in multiple-injured patients surgically treated for their spinal injury later than 24 h . Mechanical ventilation time was higher in patients surgically treated for their spinal injury later than 24 h, although this did not reach statistical significance . The prevalence of MODS or death showed no statistical difference between both groups.Comparison of multiple-injured patients surgically treated for their spinal injury within 24 h as compared to those surgically treated later than 24 h is shown in p < 0.001) and in the hospital . Mechanical ventilation time was higher in patients surgically treated for their spinal injury later than 72 h, although this did not reach statistical significance . However, patients surgically treated for their spinal injury later than 72 h had a significantly higher ISS as compared to those patients treated within 72 h . The prevalence of sepsis, MODS, or death showed no statistical difference between both groups.Comparison of multiple-injured patients surgically treated for their spinal injury within 72 h as compared to those surgically treated later than 72 h is shown in p < 0.001) and in the hospital . Although the overall injury severity was higher in the group surgically treated for their spinal injuries after 96 h, it did not reach statistical significance . Furthermore, mechanical ventilation time was significantly and almost twofold increased from 137.24 h to 250.81 h (p = 0.046). The prevalence of sepsis was also significantly higher in the group surgically treated for their spinal injuries later than 96 h . However, the prevalence of MODS or death was not higher in the group of multiple-injured patients treated for their spinal injuries later than 96 h.Comparison of multiple-injured patients surgically treated for their spinal injury within 96 h as compared to those surgically treated later than 96 h is shown in Correlation analysis revealed that there was a significant correlation between time to spinal surgery and outcome parameters . LengthsSubgroup analysis showed that the adverse effect of delayed spinal stabilization is mainly attributable to multiple-injured patients with AOSpine B-/C-type injuries. Regression analysis revealed that in patients with AOSpine A-type spinal injuries, an increased time to spinal surgery was only an independent risk factor for an increased LOS; however, in multiple-injured patients with B-/C-type spinal injuries, an increased time to spinal surgery is an independent risk factor for increased iLOS, LOS, and the development of sepsis .Comparison of multiple-injured patients with AOSpine A-type injuries compared to those multiple-injured patients with AOSpine B-/C-type injuries is shown in p = 0.138). Length of ICU stay was on average 4 days shorter, and time of mechanical ventilation roughly 90 h shorter in multiple-injured patients with A-type spinal injuries compared to those with B-/C-type spinal injuries; however, neither observations reached statistical significance . Time to spinal surgery was non-significantly prolonged in multiple-injured patients with A-type spinal injuries as compared to those multiple-injured patients with B-/C-type injuries . Multiple-injured patients with B-/C-type spinal injuries, compared to multiple-injured patients with A-type spinal injuries, showed a non-significant, higher prevalence of MODS , sepsis , and death .Multiple-injured patients with A-type spinal injuries showed a trend towards a lower overall injury severity compared to multiple-injured patients with B-/C-type spinal injuries . Length of ICU stay was significantly increased by an average of 5 days in multiple-injured patients with a thoracic spine injury compared to multiple-injured patients with a lumbar spine injury , whereas length of hospital stay showed no significant difference—although it was shorter in multiple-injured patients with a thoracic spine injury . Mechanical ventilation time was increased by an average of almost 90 h in multiple-injured patients with a thoracic spine injury compared to multiple-injured patients with a lumbar spine injury; however, this did not reach statistical significance . Time to spinal surgery was prolonged in multiple-injured patients with thoracic spine injury compared to multiple-injured patients with a lumbar spine surgery . The prevalence of MODS and death was comparable in both groups, whereas the prevalence of sepsis was significantly higher in multiple-injured patients with a thoracic spine injury compared to multiple-injured patients with a lumbar spine injury .Multiple-injured patients with a thoracic spine injury showed a similar overall injury severity compared to multiple-injured patients with a lumbar spine injury , the initial surgical burden (second hit), and the resulting systemic inflammatory response . In contIn general, our data support the concept of early posterior spinal stabilization in multiple-injured patients. Our data show that increasing time to spinal surgery in multiple-injured patients is an independent risk factor for an increased ICU and hospital stay, and that spinal stabilization later than 72 h is an independent risk factor for the development of sepsis. We consider immediate spinal stabilization, as advocated above, as spinal surgery within 24 h after trauma. Applying a 24 h cutoff to our patient population, we are able to show that multiple-injured patients with their spinal stabilization later than 24 h had, on average, a significantly longer stay of 7 days in the ICU, and a significantly longer length of hospital stay of 10 days, while having a comparable overall injury severity, as defined by the ISS, compared to those multiple-injured patients with spinal surgery within 24 h. Furthermore, the duration of mechanical ventilation was increased by approximately 30 h, and the prevalence of sepsis was significantly increased in the case of spinal stabilization later than 24 h. These adverse effects were even more pronounced for 72 h or 96 h as time cutoffs for spinal surgery. Several studies have attributed the beneficial effect of early spinal stabilization mainly to a better patient handling in the ICU, which allows, for example, for prone positioning for the improvement of pulmonary function, or even earlier in- or out-of-bed mobilization . Most ofTherefore, the “spine damage control” concept has to be interpreted with caution and should not result in the recommendation that in multiple-injured patients, every spinal injury requiring surgery should be stabilized as early as possible at almost any cost. Further subgroup analyzation of our patient population supports a more individualized treatment concept, taking into account the degree of spinal injury stability, as described with the AOSpine classification. In multiple-injured patients with AOSpine B-/C-type spinal injuries, which from a biomechanical view are unstable spinal injuries, stabilization as early as possible appears to be beneficial. In these patients, prolonged time to spinal surgery is an independent risk factor for increased length of stay in the ICU and in hospital, as well as for the development of sepsis. In contrast to these findings, the benefit of an early spinal stabilization for multiple-injured patients with AOSpine A-type spinal injuries appears to be less pronounced. In these biomechanically stable spinal injuries, a prolonged time to spinal stabilization is only an independent risk factor for an increased length of hospital stay. Although we could not observe an adverse effect of the stabilization of AOSpine A-type spinal injuries in our multiple-injured patients, this observation reduces the pressure on the trauma team to deal with AOSpine A-type spinal injuries in the acute phase. Since AOSpine A-type injuries are the predominant spinal injury pattern in our multiple-injured patient population, this may have an important impact on trauma care in the future. Although a differentiation of the spinal injury, according to the AOSpine classification, is important for decisions with regard to surgical timing, the injury type in and of itself is not an independent risk factor for adverse outcomes.Thoracic spinal injury location has been identified by other studies to adversely influence patients’ outcome ,17. Our Our data show that in our patient population, almost half of the patients (47.8%) were surgically treated for their spinal injury within 24 h, and almost ¾ of the patients (71.7%) within 72 h. Within 24 h, 50% (21/42 patients) of the total AOSpine B-/C-type spinal injuries and 39% (28/71) of the total AOSpine A-type spinal injuries were surgically addressed; thus, the surgeons already recognized the higher surgical urgency of AOSpine B-/C-type injuries. Reasons for a delayed spinal stabilization appear to be multifactorial. Regression analysis identified, in particular, a higher ISS, thoracic spine injury location, A-type injuries, and the absence of an evident neurological deficit as independent risk factors for a delay in spinal surgery.n = 35) presented with neurological impairment due to their spinal trauma. In the literature, urgent surgical spinal treatment is widely accepted in the event of any neurological impairment focusing on isolated spine trauma. The main target is the decompression of the affected nerve structures and the restoration of the correct spinal alignment. The analysis of the STASCI  study showed that a general improvement of at least two ASIA  grades is observable after early decompression within 24 h [In our population, 31% of the multiple-injured patients . Several studies confirmed that the AOSpine classification is superior to the TLICS with regard to reliability for the identification of fracture morphology ,21.In conclusion, our data support the concept of early spinal stabilization within 24 h in multiple-injured patients with AOSpine B-/C-type injuries, especially of the thoracic spine. However, in multiple-injured patients with AOSpine A-type injuries, the beneficial impact of early spinal stabilization has been overemphasized in former studies, and the benefit should be weighed against the risk of patients’ deterioration, due to the unneglectable surgical burden of spinal surgery.


Introduction: Hospitalized pediatric hematology-oncology and post-hematopoietic cell transplant (HCT) patients have frequent deterioration requiring Pediatric Intensive Care Unit (PICU) care. Critical deterioration (CD), defined as unplanned PICU transfer requiring life-sustaining interventions within 12 h, is a pragmatic metric to evaluate emergency response systems (ERS) in pediatrics, however, it has not been investigated in these patients. The goal of this study was to evaluate if CD is an appropriate metric to assess effectiveness of ERS in pediatric hematology-oncology and post-HCT patients and if it is preceded by an actionable period of vital sign changes.Methods: A retrospective review of all unplanned PICU transfers and floor cardiopulmonary arrests in a dedicated pediatric hematology-oncology hospital between August 2014 and July 2016. Vital signs and physical exam findings 48 h prior to events were converted to Pediatric Early Warning System-Like Scores (PEWS-LS) using cardiovascular, respiratory, and neurologic criteria.Results: There were 220 deterioration events, with 107 (48.6%) meeting criteria for CD, representing a rate of 2.98 per 1,000-inpatient-days. Using the first event per hospitalization (n = 184), patients with CD had higher mortality , fewer median ICU-free-days , ventilator-free-days , and vasoactive-free-days . Using vital sign data 48 h prior to deterioration events, those with CD had higher PEWS-LS on PICU admission (p < 0.001), spent more time with elevated PEWS-LS prior to PICU transfer (p = 0.008 to 0.023) and had a longer time from first abnormal PEWS-LS (p = 0.007 to 0.043). Significant difference between the two groups was observed as early as 4 h prior to the event (p = 0.047).Conclusion: Hospitalized pediatric hematology-oncology and post-HCT patients have frequent deterioration resulting in a high mortality. In these patients, CD is over 13 times more common than floor cardiopulmonary arrests and associated with higher mortality and fewer event-free days, making it a useful metric in these patients. CD is preceded by a long duration of abnormal vital signs, making it potentially preventable through earlier recognition. Delays in Intensive Care Unit (ICU) transfer for critically ill hospitalized patients have been consistently linked with worse outcomes including increasing organ dysfunction, longer ICU length of stay (LOS), and higher hospital mortality –4. SinceHospitalized pediatric hematology-oncology and post-hematopoietic cell transplant (HCT) patients are a unique patient population with more frequent deterioration and lower survival than other pediatric patients , 10, 11.The aim of this study is to evaluate if CD is an appropriate metric to assess the quality and effectiveness of hospital emergency response systems in pediatric hematology-oncology and post-HCT patients, and whether CD is preceded by abnormal vital sign allowing for intervention.St. Jude Children's Research Hospital is a 69-bed dedicated pediatric hematology-oncology hospital with an 8-bed PICU and 4-bed PICU-run intermediate care unit (IMCU) dedicated to this patient population. At the time of this study, St. Jude did not utilize a PEWS. On the hematology-oncology and HCT floors, vital signs are routinely taken by bedside nurses at least every 4 h in hospitalized patients, and more frequently in patients receiving certain therapies or those with signs of deterioration.We conducted a retrospective review of all deterioration events among hospitalized patients (defined as unplanned PICU/IMCU admissions or floor cardiopulmonary arrests) between August 2014 and July 2016. Clinical characteristics, interventions, vital signs, and nursing physical exam documentation in the 48 h prior to the event, and patient outcomes were extracted from the electronic medical record. The deterioration event start was defined as the time of PICU transfer, operating room start time (emergency procedures resulting in unplanned PICU transfer), or the time of intubation or CPR initiation on the floor (floor respiratory or cardiac arrest). PIM2 and PRISM3 were calculated based on data entered by the institution into the Virtual PICU Systems database . These were missing in 6 events due to missing VPS entries. Hospital patient days were obtained from institutional statistics reports.Critical deterioration (CD) was defined as an event requiring life-sustaining interventions  prior to or within 12 h of PICU admission. Event-free days  were defined as the number of days in the first 28 days after ICU admission or event start when the patient was alive and without the intervention. Mechanical ventilation included invasive and non-invasive (CPAP and BiPAP) ventilation. Mortality was defined as occurring during the PICU stay.PEWS-like-scores (PEWS-LS) were calculated using vital signs data in the 48 h prior to PICU admission see , 15, 16,P-values were considered significant if < 0.05, with all p-values being 2-sided. Post-hoc comparisons were also made at 1 h intervals using a Holm-simulated adjustments for multiplicity. Analysis was performed using SAS software version 9.4 for Windows .To control for multiple sampling, the first event per hospitalization was used for analysis, and events were treated as independent observations. Continuous and categorical variables were analyzed using appropriate summary statistics. Wilcoxon-Mann-Whitney, Pearson's chi-square, or Fisher's exact test were used to compare samples between groups. Trends in PEWS-LS in the 12 h prior to PICU admission were analyzed using a generalized estimating equation (GEE) Poisson model implemented in the GLIMMIX procedure of SAS  with time as a restricted cubic spline with 4 knots , CD as binary variables, and the two-way interaction. n = 2 floor cardiopulmonary arrests resulting in mortality prior to PICU admission and n = 27 unplanned PICU admissions resulting in mortality prior to PICU discharge). Characteristics of the 220 deterioration events are described in During the study period, there were 220 deterioration events  among 160 unique patients and 184 unique hospital admissions, with a range of 1–4 hospital admissions per patient see . These on = 184) was used for analysis. Clinical characteristics and mortality of these deterioration events are described in Hospital admissions were taken as the primary unit of analysis. To control for multiple sampling, only the first deterioration event per hospitalization  met criteria for CD . Patientp < 0.001), a higher maximum PEWS-LS in the 48 h prior to PICU transfer (p = 0.001), and spent a higher proportion of time with abnormal PEWS-LS prior to PICU transfer regardless of the PEWS threshold used for analysis ; this difference was more pronounced when higher PEWS-LS thresholds are used  and CD (p < 0.0001) were significant predictors of PEWS-LS, but the two-way interaction was not significant (p = 0.26). For both events with and without CD, the predicted PEWS-LS increases as time approaches PICU transfer or intervention .All 184 events had vital sign data available for analysis, with a similar duration of data in the 48 h prior to PICU transfer between those with and without CD . Out of rvention . Based oHospitalized pediatric hematology-oncology and post hematopoietic cell transplant (HCT) patients have frequent deterioration requiring PICU transfer or floor intervention resulting in high mortality . Despite this frequency of deterioration, cardiopulmonary arrests in these patients were still uncommon . Critical deterioration (CD), defined as an event requiring life-sustaining interventions  prior to or within 12 h of PICU admission, occurred more frequently, with a rate of 2.98 events per 1,000 inpatient days, representing twice the rate in this patient population compared with that reported in a large multidisciplinary pediatric hospital  . Because CD is more common than floor arrests and associated with poor outcomes and high PICU utilization, these findings support the use of CD to evaluate emergency response systems (ERSs) and hospital quality of care in pediatric hematology-oncology and post-HCT patients. While history of HCT is a known risk factor for mortality in critical illness and correlated with PICU mortality in our study, these patients did not have a higher rate of CD. These findings suggest that decisions around timing of PICU transfer were likely similar for pediatric oncology and post-HCT patients in our hospital, and CD is a reasonable quality measure in both patient populations.Beyond demonstrating the relationship between CD and poor outcomes, we sought to explore if CD events are preceded by an actionable period of abnormal vital signs, making them amenable to prevention by ERS activation. Our analysis of the 48 h prior to PICU transfer or intervention in these patients demonstrates that events with CD have significantly longer and more severe durations of vital sign changes than those without CD. Notably, patients with CD spent nearly twice the amount of time with abnormal vital signs than those without CD, regardless of the PEWS-LS threshold used in analysis. In the 12 h prior to the event, patients had documented abnormal vital signs over 10 h prior to the event, with this occurring 1.5 h earlier in those with CD; this “lead time” increased with the magnitude of vital sign abnormality (higher PEWS-LS). Similarly, the vital signs were significantly more abnormal in patients with CD, compared to those without, 4 h prior to PICU transfer or intervention. These findings suggest that CD in pediatric hematology-oncology and post-HCT patients is preceded by a prolonged period of vital sign abnormalities on the floor, which may not be appropriately recognized or acted upon by the floor team. While prior studies have demonstrated an actionable period of abnormal vital signs prior to acute deterioration events in hospitalized general pediatrics patients , no studPrevious studies in a large multidisciplinary pediatric hospital demonstrated that implementation ERS triggered by PEWS can reduce the frequency of CD . Our datThis study has several limitations. This is a single-center study in a pediatric hematology-oncology hospital. In the 2 years of study, we observed only 220 deterioration events. With the observed mortality of 13.2% we were not adequately powered to show a relationship between abnormal vital signs and mortality in our analysis (hence the need for a proxy metric such as CD). Despite the relatively small sample size, this represents one of the largest studies of deterioration in hospitalized pediatric hematology-oncology and post-HCT patients in the published literature, and our center is uniquely positioned to conduct this type of analysis in this patient population.This is a retrospective study and is subject to typical limitations of this study design. Characteristics of deterioration events and vital sign data were extracted from documentation in the clinical chart. Due to criteria for entry into VPS, six events had no PIM2 or PRISM3 for analysis and 10 events had <6 h of preceding vital sign data. This, however, represents a small minority of documented events. Similarly, PEWS-LS were calculated based on vital sign and physical exam data documented by the bedside nurse during routine assessment; due to close proximity from hospital admission to PICU transfer, not all patients had 48 h of data available for analysis. To account for intermittent vital sign documentation, we carried forward documented data until a new observation was recorded. It is possible that this method missed more frequent vital sign changes than that which was documented by the beside nurse in the electronic medical record. However, as these patients were actively deteriorating during this time period, vital signs were likely worsening, rather than improving, and this method likely underestimated the true duration of vital sign abnormalities, making these results a conservative estimate of the true extent of abnormalities prior to PICU transfer or floor intervention.The PEWS-LS was calculated using cardiovascular, respiratory, and neurologic vital signs, and physical exam findings. Some PEWS scoring tools validated in pediatric hematology-oncology patients use the added criteria of “nursing concern” and “family concern” to augment the objective components of the scoring tool , 15. AddFinally, we can only speculate that the long duration of abnormal vital signs prior to CD suggests these events are potentially preventable through earlier intervention. However, there is an abundance of evidence that delays in ICU transfer for patients with clinical changes increases mortality –4, 12, aHospitalized pediatric hematology-oncology and post-HCT patients have frequent deterioration resulting in a high mortality. Critical deterioration in these patients is over 13 times more common than floor cardiopulmonary arrests and is associated with higher mortality and fewer event-free days, making it a useful metric for evaluating the quality of inpatient care and performance of emergency response systems. A protracted period of unrecognized abnormal vital signs on the floor prior to PICU transfer or floor intervention in these patients may be contributing to high rates of CD and high mortality. Systems for early identification of vital sign changes may improve hospital outcomes in these high-risk patients.The datasets generated for this study are available on request to the corresponding author.This study was approved by the Institutional Review Board at St. Jude Children's Research Hospital. Written informed consent was not required to participate in the study in accordance with national legislation and institutional requirements.Conceptualization and funding acquisition: AA and RM. Data curation, project administration, and validation: AA, JG, AC, and GK. Formal analysis, visualization, and writing—original draft: AA, JG, and GK. Investigation and methodology: AA, JG, GK, and RM. Resources: AA, GK, and RM. Software: JG and GK. Supervision: GK and RM. Writing—review and editing: AA, JG, AC, GK, and RM. All authors have reviewed and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.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.