Fiberglass-reinforced plastics (FRP) manufacturing has been related to cases of severe airway obstruction and elevated risk of respiratory mortality. But the specific job content risk is not clear. This study evaluated the respiratory health effects of the FRP lamination process.A questionnaire was used to evaluate respiratory symptoms of workers in two yacht-building plants. Pre-shift (07:30–08:30 hours) and post-shift (17:00–18:00 hours) lung function was measured, while post-shift induced sputum was collected on the first day of the week. The participants were grouped into FRP laminators and non-laminators. Linear and logistic regression was used to investigate the effects of the lamination process on lung function.Laminators had a higher prevalence of chronic cough, lower pre-shift forced expiratory volume in first second (FEV1) and FEV1/force vital capacity (FVC) (-3.3% and -1.5%), lower post-shift FVC and FEV1 (-3.6% and -4.9%), and larger post-shift reduction of FVC (-2.1%) compared to non-laminators. The laminators also had higher risk of early obstructive and overall (obstructive plus restrictive) lung function impairment, and post-shift reduction of FVC >10% [odds ratio (OR) 5.98, 4.98, and 3.87, respectively). They also had higher percentages of neutrophils and lymphocytes in the induced sputum.Laminators should undergo regular check-ups of respiratory symptoms and lung function. Further toxicologic studies are warranted to identify the specific causal agent in the FRP lamination process. In 2013, eight workers involved in laying up fiberglass woven roving with polyester resins were reported to have obliterative bronchiolitis, a severe irreversible airway obstructive disease involving the small bronchioles . AnotherAside from case reports and death registry analysis, epidemiologic surveys using lung function tests and other biomarkers can provide pathophysiologic information for non-diagnosed and subclinical cases. Epidemiologic studies on the respiratory health of workers in fiberglass-reinforced plastics (FRP) manufacturing remain limited. Because styrene is one of the most abundant volatile compounds used in FPR and is the active diluent of polyester resin (36–45% of weight concentration), it is a major concern . PreviouIdentifying the health risk of a specific group with similar exposure is an important step in occupational health. In the light of previous case reports, all of which involve manually wiping the glue and laying up the FRP, we conducted this study to evaluate the respiratory effects associated with the lamination process.A cross-sectional study on two yacht-building plants in Taiwan was conducted in 2011 (plant A) and 2015 (plant B). All the employees (68 in the plant A and 54 in the plant B), including administrative personnel, were invited to participate. The Institutional Review Board of the National Taiwan University Hospital approved the study protocol (201110017RC), and each participant provided informed consent. Pre-shift (07:30–08:30 hours) and post-shift (17:00–18:00 hours) lung function was measured, and post-shift induced sputum was collected on Mondays – the first workday of the work-week. Each participant received two measurements of lung function and one collection of sputum. All of the participants answered a questionnaire that provided demographic information, respiratory symptoms, cigarette smoking habits, and medical diagnoses.3).Aerial concentrations of styrene were measured during the study. In plant A, first, we performed stationary monitoring with the use of photo-ionized detector (PID) to measure concentrations of total volatile organic compounds near the lamination process paired with air sampling by canisters for 40 minutes. Canister-sampled air was further analyzed for concentrations of various chemicals, including styrene, by GC-MS. Eight repeats of PID-canister-paired monitoring were done, and the styrene estimation formula by PID values was obtained. Next, we measured total volatile organic compounds by PID for 10 minutes near the breathing zone of laminators who were doing lamination. A total of 36 person-times PID monitoring was done among 13 laminators. Their styrene exposures were then estimated by PID values. In plant B, styrene was sampled by personal active samplers with active carbon tubes for seven hours during work and analyzed by GC-FID method. We took 47 measurements, including 9 for lamination work, 12 for administration, 9 for woodwork, 6 for grinding work, and 11 for maintenance. Concentrations of styrene were expressed as parts per million (ppm)  usually stood inside the wooden yacht mold and repeatedly used rollers to impregnate the resin and rolled it onto the glass fiber roving layer-by-layer. Sometimes the laminators needed to enter more restricted compartments for lamination. Employees engaged in grinding work used a hand-held grinder to polish the surface of the hull. Woodworkers were responsible for the manufacture of wood-related furniture and facilities inside the hull. Woodworkers were usually exposed to wood dust and sometimes paint. The administrative staff’s office in plant A was located in a building separate from the yacht construction factory, while, in plant B, it was located in the same building structure. Maintenance workers were responsible for the maintenance of water, electricity, and various machinery and equipment in the factory, and their working place was not fixed inside the building of lamination work. Regarding personal protective equipment, plant A provided a half-face mask with a cartridge for the laminators, but plant B only used general cotton or activated carbon masks. During the surveys, due to the hot weather, many workers did not use the respirator correctly.Spirometry was measured based on the guidelines of the American Thoracic Society . Each paSputum was induced through increasing concentrations of saline , as described by Perng et al . The proThe participants were grouped into laminators and non-laminators . Between-group differences in demographic information and respiratory symptoms were analyzed by Chi-square, Fisher exact test, or Student’s t-test. Between-group differences in differential count in the induced sputum were analyzed by Wilcoxon rank sum test.Linear and logistic regressions were used to evaluate the relationship between the FRP lamination process (laminators/non-laminators), tenure of lamination work (in years), lung function parameters, and patterns of ventilatory defects, with adjustments for age, sex, educational attainment, tenure, current smoking, past smoking, and cumulative smoking amount. To examine whether sputum differential cell counts could be an intermediate biomarker for functional phenotyping of the respiratory system, we used linear regression to assess the association between the percentage of each cell type with lung function parameters. Statistical significance was set at P<0.05.Overall, the study participants consisted of 113 employees, 63 from plant A and 50 from plant B. The proportions of female workers and educational attainment <13 years were higher among the laminators than among the non-laminators . There wGeometric mean concentrations of styrene measured for laminating work amounted to 7.5 ppm in plant A and 16.5 ppm in plant B, ie, approximately 30–66 times higher than the geometric mean of 0.2–0.3 ppm measured (in plant B only) for the other jobs . In geneLaminators had a statistically higher prevalence of chronic cough than non-laminators . Laminatwww.sjweh.fi/show_abstract.php?abstract_ id=3924, table S2). We further stratified all participants in to three groups, non-laminators (never) and those with lamination tenure < or >6.14 years (the median among laminators), and found that only those with lamination tenure <6.14 years had significantly higher risk of obstructive and overall (obstructive plus restrictive) impairments (table S3).The pre-, post-, and between-shift changes of lung function revealed that after adjustments for confounding factors, laminators had significantly lower pre-shift FEV1 and FEV1/FVC, lower post-shift FVC and FEV1, and larger post-shift reduction of FVC compared to non-laminators . In termSputum was collected from 51 out of 63 participants in plant A: 12 could not produce sputum after hypertonic saline inhalation, while 2 were excluded due to inadequate sputum quality . Laminators had higher percentages of neutrophils and lymphocytes, and lower percentage of macrophages than non-laminators . The perIn this cross-sectional study in two FRP manufacturing plants, we found that laminators chronically exposed to moderately high styrene levels exhibited an excess of respiratory complaints (mainly cough), impaired spirometry and signs of pulmonary inflammation when compared to non-laminators.The prevalence of chronic cough  was higher among laminators than non-laminators, even though the former had fewer smokers. Cough was a more common complaint during work at daytime and before sleep at night, but with recovery the next morning. Airway symptoms (cough or wheeze) also improved during holidays or days-off. These respiratory symptoms are suggestive of asthma and may explain why such affected workers were likely to be treated as asthmatic patients, thereby ending up with irreversible fixed airway obstructive disease, as noted in published reports , 2. ProgThe laminators had an elevated risk of obstructive lung function impairment. This is consistent with previous case reports and epidemiologic studies , 2, 8, 9Workers involved in the FRP lamination process using the open-molding method are usually exposed to the highest levels of evaporated chemicals from polyester resins . Aside fIncreased cross-shift reduction in FVC suggests restrictive lung function effects of acute exposure to FRP lamination-related substances. However, the pathophysiology is not identified or described in this study because of the lack of information on total lung capacity and post-bronchodilator lung function. It can only be speculated that the change may be related to processes in the small rather than large airways (mainly FEV1/FVC). Small airway diseases can present as a reduction in FVC due to occlusion or dynamic collapse of small bronchioles , 20. SomSusceptibility to bronchiolitis obliterans related to FRP chemicals is unknown, although some relevant clues have been provided in previous literature. First, only a small number of cases are reported to have severe obstructive lung disease and the symptoms often manifest shortly after employment 6–12 months), whereas other co-workers do not have the same symptoms or illness even under similar working conditions 2 months,, and thiThe present study revealed an elevated percentage of sputum neutrophils rather than eosinophils among laminators. This is consistent with results by McCague et al  who showThe elevated percentage of induced sputum lymphocytes among laminators, and its association with post-shift lung capacity, suggests that lymphocytes associated inflammation also play a role in the laminating related respiratory effect. A previous study has demonstrated an increased lymphocyte percentage in induced sputum in several interstitial lung diseases  in contrThe percentage of sputum macrophages in laminators was lower than that in non-laminators. Alveolar macrophages usually play a defensive role in respiratory exposure to pathogens and particulate matters . A previThis study has some strengths. First, we conducted field research before and after work on Monday, which minimized the effect of exposures on the previous days. Therefore, the impact on preshift lung function is likely to be related to chronic exposures and the effect on cross-shift lung function changes linked to acute exposures. Second, the laminators who participated in this study usually remained in hand lay-up work in FRP manufacturing rather than moving around different kind of processes, which minimized the interference from other exposures, such as wood dust, painting, and FRP grinding dust. Third, this study included exposed and non-exposed groups in the same plant, which minimized bias related to environmental exposure .Some limitations are noteworthy. First, the study’s cross-sectional design may have caused an underestimation of the health hazards due to the healthy worker or healthy worker survival effect. Airway symptoms, such as cough or dyspnea, may alert workers to leave work. Since we have already observed the effects on lung function, the healthy worker effect may have prevented us from observing more severe cases of impaired respiratory function. Second, grouping laminators into a single exposure group may underestimate the health effects in the extremely high exposure groups, such as those more commonly working in an enclosed structure or with large surface lamination processes. The incomplete and differential measurement of styrene in the two plants prevented us from assessing the exposure–response relationship for the entire data set. Finally, as this is a simple cross-sectional study without long-term follow-up, reversed causality should be cautiously considered.Workers using the hand lay-up method for FRP lamination have higher risk of chronic cough, obstructive lung function impairment, cross-shift drop in lung function, and elevated neutrophilic and lymphocytic inflammation of the airways. Until the true causal agent used in the lamination process is identified and replaced, laminators should undergo regular health examinations with focus on respiratory symptoms and lung function. Workers should also use adequate personal protective equipment.


Are there differences in survivorship between top-ranked cancer hospitals and affiliates that share a top-ranked hospital’s brand?In this cohort study of 119 834 patients who underwent surgical treatment for esophageal, gastric, lung, pancreatic, colorectal, and bladder cancer, risk of 90-day mortality after complex cancer treatment was higher and long-term survival was inferior at affiliate hospitals.These findings suggest that quality improvement efforts are needed to address important differences in survival between top-ranked cancer hospitals and brand-sharing affiliate hospitals. This cohort study examines short-term survival outcomes among patients who receive cancer treatment at top-ranked cancer hospitals compared with those who receive cancer treatment at affiliate hospitals. Hospital networks formed around top-ranked cancer hospitals represent an opportunity to optimize complex cancer care in the community.To compare the short- and long-term survival after complex cancer treatment at top-ranked cancer hospitals and the affiliates of top-ranked hospitals.US News and World Report) were compared with outcomes at affiliates of top-ranked cancer hospitals . Data were analyzed from July through December 2019.This cohort study was conducted using data from the unabridged version of the National Cancer Database. Included patients were individuals 18 years or older who underwent surgical treatment for esophageal, gastric, lung, pancreatic, colorectal, or bladder cancer diagnosed between January 1, 2012, and December 31, 2016. Patient outcomes after complex surgical procedures for cancer at top-ranked cancer hospitals  was compared using logistic regression, and the association of affiliate status with long-term survival was compared using time-to-event models, adjusting for patient demographic, payer, clinical, and treatment factors.P < .001). Adjusted long-term survival following cancer treatment at affiliate hospitals was only 77% that of top-ranked hospitals . The survival advantage was not fully explained by differences in annual surgical volume, with both long- and short-term survival remaining superior at top-ranked hospitals even after models were adjusted for volume.Among 119 834 patients who underwent surgical treatment for cancer, 79 981 patients (66.7%) were treated at top-ranked cancer hospitals  and 39 853 patients (33.3%) were treated at affiliate hospitals . In a pooled analysis of all cancer types, adjusted perioperative mortality within 90 days of surgical treatment was higher at affiliate hospitals compared with top-ranked hospitals (odds ratio, 1.67 ; These findings suggest that short- and long-term survival after complex cancer treatment were superior at top-ranked hospitals compared with affiliates of top-ranked hospitals. Further study of cancer care within top-ranked cancer networks could reveal collaborative opportunities to improve survival across a broad contingent of the US population. Receiving complex cancer treatment from an insufficiently prepared hospital  can expose a patient to a 4-fold increase in risk of death from surgical complications.8 National ranking systems, such as those published in US News and World Report (USNWR),9 can support hospital reputation for safety and quality. Such national ranking systems can influence patients’ hospital choice,11 and ultimately affect hospital market share.12A hospital’s reputation for safety and quality  is a major consideration as patients evaluate hospitals for cancer care.13 This brand-sharing has the potential to influence patients’ hospital preferences. In a recent nationally representative survey in the US, half of respondents believed that the safety, quality, and cure rates of complex cancer treatment would be the same at top-ranked hospitals and their affiliates.14 Furthermore, respondents indicated that affiliation with a top-ranked cancer hospital would increase their preference for a local hospital.15 At the same time, a 2019 study of Medicare enrollees13 found that mortality after complex surgical procedures to treat cancerwas 1.4-fold higher at affiliate hospitals compared with the top-ranked hospitals whose brands they shared.Top-ranked cancer hospitals have increasingly shared their brands with unranked hospitals through networks of affiliations.affiliates) in the National Cancer Database (NCDB). Our objective was to establish a baseline differential of outcomes to inform future quality improvement efforts that leverage the network infrastructure and potential collaborations between programs.We sought to examine short- and long-term outcomes across hospitals participating in top-ranked networks among patients 18 years or older. Quality as well as short-and long-term survival after complex surgical procedures to treat cancer were compared between top-ranked hospitals and affiliates of top-ranked hospitals  reporting guideline.The National Cancer Database (NCDB) is a prospective registry of cancer care occurring at Commission on Cancer (COC)–accredited hospitals, capturing 72% of newly diagnosed malignant tumors in the US.USNWR at least once between 2013 and 2016 were eligible to be analyzed as the top-ranked cohort. The USNWR rankings were chosen because they are widely recognized by the public, have been shown to influence patient choice,10 and potentially have the highest correlation with quality among publicly available indicators.18 Of note, there is approximately 75% concordance between designation by National Cancer Institute, and the USNWR top 50 cancer hospital status. Brand-sharing affiliates of top-ranked hospitals were identified as hospitals that (1) were affiliates of 1 of the top-ranked hospital in the American Hospital Association’s annual survey and (2) included the name of the top-ranked hospital  in their web presence, as described previously.13 Both top-ranked hospital cohort and the affiliate cohort performing complex surgical procedures to treat cancer were further restricted to only those accredited by the COC.Hospitals that were ranked as being in the top 50 cancer hospitals by Patients 18 years and older who had undergone a complex surgical procedure as treatment for colorectal, lung, pancreatic, gastric, esophageal, or bladder cancer between January 1, 2012, and December 31, 2016, were eligible. The complex surgical procedures to treat cancer included colectomy , proctectomy, esophagectomy, pulmonary lobectomy, pneumonectomy, pancreaticoduodenectomy (Whipple), gastrectomy , and cystectomy. Surviving patients with less than 90 days of follow up (5.5% of patients) were excluded from the main analysis, but they were included in sensitivity analysis.19 At the same time, we wanted to consider procedures involving different anatomic regions, and thus likely different surgical teams. Combined, the studied procedures represent more than 80% of complex cancer treatments in the US and are similar to those that have previously been studied as complex cancer treatments.21These complex procedures were chosen based on 2 perspectives. First, we wanted to focus on procedures with an operative mortality that exceeded 2%, a metric previously described as an indicator of high-risk cancer treatment.American Joint Cancer Committee, Seventh edition22), tumor grade, insurance type , median income quintiles by zip code, and history of a prior malignant tumor (included as an important adjuster based on our prior work23). Several of the procedures had variations that involved removing surrounding structures, so an extended modifier was added to denote additional complexity in case one cohort performed more complex procedures than the other.The primary independent variable was hospital type, coded as whether the surgical procedure was performed at an affiliate hospital. Additional covariates were patient age , sex, modified Charlson-Deyo comorbidity score , year of diagnosis, administration of chemotherapy or radiation, pathological stage , adherence to COC quality metrics, surgical margins, 30-day unplanned readmission, 90-day mortality , and survival from the date of diagnosis . For survival analysis, patients were censored at death or day of last contact in the NCDB. The NCDB only captures readmissions in which the patient was readmitted to the same hospital where the surgical procedure was performed . Because patients are less likely to be readmitted to the hospital that performed surgical treatments as the travel distance increases, the analysis of readmissions was restricted to patients in both cohorts who traveled less than 50 miles for cancer treatment. For the analysis of the number of days between diagnosis and treatment , only patients in whom surgical treatment was the first treatment were analyzed. This restriction was imposed because induction chemotherapy and radiation regimens may vary in duration and toxic effects and could obscure a time-to-treat calculation2 and Wilcoxon tests.Patient demographic, clinical, and treatment characteristics were summarized by affiliation type. Unadjusted 3-year survival was evaluated using Kaplan-Meier curves, as well as 5-year survival as a sensitivity analysis. Quality metrics were compared across affiliate status using χTo assess differences in 90-day mortality between affiliates and top-ranked hospitals, we estimated a series of random effects logistic regression models. A separate model was estimated for each procedure and 1 for all procedures pooled. Effects are reported as odds ratios (ORs) representing risk of 90-day mortality for patients at affiliate hospitals.25 Therefore, we evaluated parametric time-to-event models using Akaike Information Criteria, identifying the γ distribution as providing the best fit.26 Mixed-effects γ models for each cancer type included the same risk adjusters as for 90-day mortality, with additional indicators in the lung, colon, and gastric models for procedure type. The pooled model also included indicators for cancer type. Time ratios (TRs) were reported to represent relative total survival time for patients at affiliate hospitals compared with those at top-ranked hospitals.To assess differences in long-term survival, we estimated time-to-event models for each cancer type and all cancers pooled. Schoenfeld residual tests rejected the proportional hazards assumptions for all cancer types and all types pooled.To account for clustering effect, all models included nested random intercepts that were allowed to vary across hospitals. Variance decomposition analysis indicated that there was no additional correlation within networks. To account for potential selection bias, we estimated propensity models in which the outcome was treatment at an affiliate hospital. A separate model was estimated for each procedure or cancer type and used to estimate a propensity score; these propensity scores were incorporated as covariates in all adjusted models  and Stata statistical software version 16 (StataCorp). Several sensitivity analyses were performed. Annual surgical volume for each procedure at each hospital was incorporated into adjusted models. We analyzed 30-day, instead of 90-day, mortality. We performed our analysis excluding the 3 largest networks. We also performed the analysis restricting to networks in which both top-ranked hospitals and their specific affiliates were represented. We further stratified models by age (<65 year vs ≥65 years). A further analysis was performed including administration of adjuvant chemotherapy in patients with gastric cancer patients, which is not a COC quality measure.A total of 56 top-ranked hospitals and 206 affiliates were included in analysis  (eTable 1 in the P < .001) and preoperative radiation  and to have traveled farther distances between home and hospital . A staging or diagnostic procedure was performed in 60.9% of patients at top-ranked hospitals and 61.5% of patients at affiliates.Among the modest differences in patient sociodemographic characteristics and health across hospital cohorts, a greater proportion of patients at affiliate hospitals were 75 years or older  and the differential varied by procedure (eTable 2 in the P < .001). Additional patient and hospital characteristics are described in eTable 1 in the Top-ranked hospitals tended to have higher median (IQR) annual procedural volumes (68.2 [37.8-111.4] procedures) compared with affiliates (31.8 [15.0-47.6] procedures) (P < .001). Furthermore, the interval between diagnosis and surgical treatment was longer for patients at the top-ranked cancer hospitals than those at affiliates  and varied by procedure  and lung cancer  (P = .72), but both were considerably less adherent than what was observed for the COC chemotherapy quality measures.Adherence with COC quality measures was assessed for patients with lung or colon cancer, as they were cared for by the largest number of hospitals. Affiliates and top-ranked hospitals were similarly adherent with the adjuvant chemotherapy measures. However, top-ranked hospitals were more likely than affiliate hospitals to analyze the recommended number of lymph nodes for colon cancer  . Adheren < .001) . AdherenP < .001) (P = .38), to total colectomy .Overall, unplanned postoperative 30-day readmission rates were similar across hospital types . The una < .001) . The adjUnadjusted 3-year survival was significantly superior at top-ranked hospitals for each cancer type  (P < .001)  . The magP < .001) or long-term  survivorship . Second, all adults were considered, whereas the study by Hoag et al was limited to adults older than 65 years. Third, our adjusted models were enhanced by the inclusion of more tumor attributes  and treatment data . Overall, our findings may serve to fortify concerns that considerable differences in perioperative safety may exist between top-ranked hospitals and affiliates.This cohort study found that short- and long-term survivals after complex cancer treatment were superior at top-ranked cancer hospitals compared with brand-sharing affiliates. The nearly 1.7-fold difference in probability of 90-day mortality risk at affiliates mirrors a 2019 report by Hoag et alWe found that long-term outcomes were superior at top-ranked hospitals for each cancer type studied. Importantly, the survival advantage was observed for colon cancer, which is commonly managed in the community . The differences in long-term survival were not entirely explained by advantages in surgical mortality, given survival at top-ranked hospitals was superior even when deaths occurring in the perioperative period were excluded . This suggests differences in care may include nonsurgical as well as surgical components.28 and long-term survival.31 However, sensitivity analyses demonstrated that differences in surgical volume did not fully explain the differences in survival. That is, while volume adjustment did mitigate a portion of the differential , the overall finding of inferior survival at affiliates remained. This is consistent with our findings when volume was included in our Medicare database study.13 It should be noted that our study was not designed to explain the etiological origin of the differential, simply to assess the magnitude of the differential. We recognize that for some procedures in some networks, the optimal survival may require lower volume hospitals to stop performing certain operations.The top-ranked hospitals performed more than 2-fold the annual volume of affiliate hospitals, which is potentially important because higher surgical volumes have been associated with advantages in surgical mortality,32 compliance with COC chemotherapy and lymph node measures17) were similar between hospital cohorts. The interval of time between diagnosis and surgical treatment, which is potentially associated with survival,35 favored the affiliate hospitals . This may reflect a greater travel distance for patients being cared for at top-ranked hospitals or workflow congestion from treating higher patient volumes at top-ranked hospitals. If affiliates performed more emergency surgical procedures , this could decrease the time to treatment at affiliates and could also negatively affect survivorship . While the NCDB does not capture emergent surgical treatment status, emergent treatments were excluded from our Medicare study, and affiliate patients remained 1.4-fold as likely to die within 90 days of surgical treatment.13A number of quality metrics known to affect long-term survival . By demonstrating that brand-sharing does not equate to quality sharing, we hope to motivate efforts to leverage unique levels of connectivity and collaboration provided by networks. The onus is now on the medical community to analyze these survival differences to identify opportunities to improve care across the networks.36 Therefore, we may be studying the better affiliates, which may minimize the differential. Another limitation is that cause of death and date of recurrence data are not available. A proportion of patients likely died of noncancer causes, unrelated to their surgical or oncological care , and it is plausible that differences in noncancer causes drive the differences in overall mortality. On the other hand, the unadjusted survival focused in the first 3 years after cancer treatment, a period in which the risk of cancer recurrence would be at its highest. Related to this, the completeness of the staging evaluation is unknown. It is possible that top-ranked hospitals performed more accurate staging evaluations, which could favorably affect the survival in the top-ranked cohort. Since NCDB does not capture use of imaging, we examined the use of staging and diagnostic procedures as a surrogate for the staging workup and found the frequency to be similar between top-ranked hospitals (60.9%) and affiliates (61.5%). Additionally, the nature of the affiliation relationship  or duration is unknown. In our previous study of top-ranked hospitals networks,13 the median (IQR) duration of affiliation by end of study was 51 (27-137) months. That being said, patients are unlikely to have a comprehensive understanding of the nature of an affiliation relationship when they are potentially influenced by brand-sharing.There are several limitations to our study. In addition to the limitations typical of observational studies, selection bias may exist, as patients chose hospitals, and this choice may be associated with patient factors that are also associated with their outcomes. Although we addressed this by incorporating propensity score adjustment in our models, there may be confounders that were not available . In addition, the study was limited to patients undergoing surgical treatment at COC-accredited hospitals, and COC accreditation has been associated with better outcomes.These findings suggest that safety and potentially the effectiveness of the overall care of patients undergoing complex cancer treatment appears to be superior at top-ranked cancer hospitals compared with affiliate hospitals. Additional efforts to characterize survival within networks around top-ranked cancer hospitals could identify collaborative approaches to improve care and inform patient choice for hospitals.


N = 110,072) were followed in national registers from their last contact with the CAMHS, until end of 2015. Exposure was self-harm as reason for contact, outcome measures were: alcohol-/substance use disorder, psychiatric hospitalization, non-violent or violent crime, and suicide. Differences in outcomes rates between exposed versus unexposed males, and exposed versus unexposed females, were examined using Cox regressions, expressed as hazard ratios (HR) with 95% confidence intervals (CI). Median follow-up time was 5.8 years . Self-harm was documented in 2.2% (N = 1241) males and 8.7% (4716) females. Exposed individuals had higher HR for all outcomes as compared with unexposed individuals of their own sex. Exposed females had more pronounced risk for drug use disorder  compared with exposed males . Both males and females who had engaged in self-harm had elevated risks for future suicide. Adjusting for socio-economic status and age at start of follow-up only marginally affected the associations. Females and males with self-harm had similarly elevated risk for suicide, and self-harm was also an important risk marker for other adverse outcomes within both sexes.Little is known about sex differences in outcomes of self-harm, and there are inconclusive results concerning the association between sex, self-harm, and suicide attempts. The aim of this study was to explore sex differences in outcomes of self-harm in adolescence. In this cohort study, all individuals (0–17 years) enrolled at the child- and adolescent mental health services (CAMHS) in Stockholm between 2001 and 2015 ( Self-harm refers to all self-directed harmful acts, regardless of suicidal intent  , 2, and While both males and females engage in self-harm, studies on sex differences in terms of long-term outcomes are sparse and available findings are inconclusive. In general, suicide attempts are more common among females, while suicides are more common among males . Some stExcept from a large multi-center study from England that included over 5000 individuals presenting to hospitals due to self-harm , most loICD-9: E950-9 and ICD-10: X60-84, or; ICD-9: E980-9 and ICD-10: Y10-34) in the Swedish National Patient Register as a measure for self-harm exposure. Within the clinical practice of Child and Adolescent Mental Health Services (CAMHS) in Stockholm , self-harm is not consistently assigned X- or Y-diagnoses, and, therefore, will not be noticed in the National Patient Register as such. Therefore, albeit having large samples, Swedish register studies using the X- or Y-diagnosis as exposure for self-harm will most likely focus only on the subgroup of patients who self-harm severely enough to receive medical attention, but may not include the adolescents with less severe versions of self-harm or suicidal behaviours, or those who are in early phases of self-harm processes. In a previous study, our group addressed this gap by making use of a patient cohort identified through a regional clinical care register of patients who had contacted the CAMHS in the Stockholm County, where exposure to self-harm was documented by a clinician as a reason for contact with the mental health services [However, a limitation with studies based on ICD-codes is that only the more severe cases are usually included. Both of the previously mentioned studies used a registered record of an ICD-code  associated with care contact due to self-harm during adolescence, in a large enough sample to explore sex differences.All Swedish residents are at birth, or immigration, assigned a personal identification number. This number is used by different governmental agencies for collecting data, including the health care system and various national registers. The data are organized and held by the governmental agency, Statistics Sweden. In this study we used outcome data from: (1) the National Patient Register that holds information on all psychiatric in- and outpatient specialist care (with complete coverage since 2006), including diagnostic codes according to the ICD-10 1997–2015; (2) the National Crime Register that holds data on all criminal convictions in Swedish lower courts; (3) the Register of Persons Suspected of Offenses with data on suspicion of a crime after completed investigation by police or other authority; (4) the Multi-Generation Register with information on family relations; (5) the Cause of Death Register which holds information on all deaths and the registered cause of death; and (6) the Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA) that contains information on education and employment.Data on exposure were collected from a regional care register (the Pastill Register) that holds data on each patient at CAMHS Stockholm. CAMHS provide specialist-level psychiatric care to all inhabitants under age 18 in the Stockholm County. Apart from the public CAMHS, there are also some private caregivers who are commissioned by the County Council, but approximately 90% of the care budget goes to the public CAMHS. The Pastill Register was introduced in 1999, and since 2001, it holds information on contact reason, treatment provided, mental disorders according to the ICD-10, psychotropic medications, psychosocial problems, and global functioning on each patient at CAMHS. Data on contact reason and psychosocial problems are manually documented in Pastill by the clinician, while the remaining data are derived directly from the digital charts. The Pastill Register was linked to Swedish national registers using the personal identification number.N = 110,072). The cohort was followed for the outcomes from the last registered contact with CAMHS until the end of 2015.The study cohort consisted of all individuals who were enrolled at CAMHS in Stockholm between 2001 and 2015  contact reason(s) in the Pastill Register. Contact reason was assigned by the responsible clinician at the time. During the early phases of the observation period, there was no specific documentation in the Pastill Register on suicidal intent; thus, individuals categorized as exposed could have presented with either non-suicidal or suicidal self-harm.The outcome measures in the national registers were (1) a diagnosis of alcohol or substance use disorder ; (2) an inpatient psychiatric care (regardless of reason); (3) having been suspected or convicted of a non-violent or violent crime; and (4) death by suicide.Analyses were adjusted for the potential effect of socioeconomic status, using the mother’s highest level of education as a proxy, and for age at start of follow-up (last registered contact with CAMHS).Differences in outcomes rates were analysed between: (1) exposed males versus unexposed males; and (2) exposed females versus unexposed females. Differences in outcome rates were examined using Cox regressions and expressed as hazard ratios (HR) with 95% confidence intervals (CI). The analyses were first made without adjustments (crude), then with adjustments for socioeconomic status and age at start of follow-up. The proportional hazards assumption was not violated in any analyses .Substance use disorder was further divided into separate drug classes . Differences in outcomes rates after adjustments were analysed as above.N = 1241) of all male and 8.7% (4716) of all female patients. Exposed males and females had elevated hazard ratios for all outcomes as compared with unexposed patients of their own sex. Females with self-harm compared to females without self-harm had an excess risk for drug use disorder  relative to males with self-harm versus males without self-harm . After adjusting for socioeconomic status and age at start of follow-up, all associations were somewhat diminished, but remained significant. Both males and females who had engaged in self-harm had elevated risks for future suicide. All results are presented in Table All results are presented in the appendix, Table In this study, we investigated adverse outcomes in a clinical cohort of males and females who contacted care within the specialized mental health services in Stockholm, where a clinician had documented self-harm as one of the contact reasons. The main finding was that males as well as females exposed to self-harm before age 18 had similar—and higher—risk profiles with regard to adverse outcomes compared to patients without documented self-harm. Both males and females with self-harm had elevated risks for alcohol and drug misuse, subsequent psychiatric inpatient care, criminality (non-violent as well as violent), and suicide, as compared with other patients.Our results provide further evidence of the associations between self-harm and later adverse outcomes previously found in a study with a smaller sample of former CAMHS patients , as wellThe other important aspect of this study is that there was a risk of later adverse outcomes associated with self-harm within each sex, regardless of general differences and similarities between sexes. Although more males than females commit crimes, self-harming male patients had over four times higher risks of being convicted of a crime than male patients without self-harm, and for self-harming females that risk was nearly six times higher. Previous research show that females with SH exhibit high risks for violence  and subsPrevious research shows that across studies, women are more likely to report a history of self-harm than men, with larger sex differences for clinical samples . This raThis study may add to the knowledge concerning self-harm and sex; however, the study has limitations. Self-harming acts are often underestimated in clinical care  and desp


Restoration of epicardial coronary blood flow, achieved by early reperfusion with primary percutaneous coronary intervention (PPCI), is the guideline recommended to treat patients with ST-segment-elevation myocardial infarction (STEMI). However, despite successful blood restoration, increasing numbers of patients develop left ventricular adverse remodelling (LVAR) and heart failure. Therefore, reliable prognostic biomarkers for LVAR in STEMI are urgently needed. Our aim was to investigate the role of circulating microRNAs (miRNAs) and their association with LVAR in STEMI patients following the PPCI procedure. We analysed the expression of circulating miRNAs in blood samples of 56 patients collected at admission and after revascularization . The associations between miRNAs and left ventricular end diastolic volumes at 6 months were estimated to detect LVAR. miRNAs were also analysed in samples isolated from peripheral blood mononuclear cells (PBMCs) and human myocardium of failing hearts. Kinetic analysis of miRNAs showed a fast time-dependent increase in miR-133a, miR-133b, miR-193b, miR-499, and miR-320a in STEMI patients compared to controls. Moreover, the expression of miR-29a, miR-29b, miR-324, miR-208, miR-423, miR-522, and miR-545 was differentially expressed even before PPCI in STEMI. Furthermore, the increase in circulating miR-320a and the decrease in its expression in PBMCs were significantly associated with LVAR and correlated with the expression of miR-320a in human failing myocardium from ischaemic origin. In conclusion, we determined the time course expression of new circulating miRNAs in patients with STEMI treated with PPCI and we showed that miR-320a was positively associated with LVAR.  ST-segment-elevation myocardial infarction (STEMI) is considered the most common and severe acute myocardial infarction (AMI) . AccordiLVAR remains difficult to predict  even if All procedures involving study subjects were performed according to the principles published by the declaration of Helsinki and its amendments or comparable ethical standards. The study was approved by the local Ethics Committee on Human Research at the University Hospital “Virgen del Rocio” of Seville and the University Hospital of “Virgen de la Victoria” of Málaga . Strengthening the reporting of observational studies in epidemiology (STROBE) guidelines were followed to report our findings .All study subjects voluntarily participated and signed an informed consent form. As depicted in First, blood samples were extracted after catheter insertion in the radial artery before initiation of the PPCI procedure. These samples represented the pre-reperfusion time point 0 h. Additional blood samples were collected at 3, 6, 12 and/or 24 h after culprit vessel opening. Additional blood samples were collected 1 month after the ischaemic event. Echocardiography was performed to determine ventricular ejection fraction and systolic and diastolic left ventricular diameters and volumes before patient discharge and 6 months after PPCI to determine the possible development of LVAR. LVAR was defined as an increase of at least 20% in left ventricular end-diastolic volume (LVEDV) with left ventricular ejection fraction less than 50%, as defined according to current clinical indications .Serum was obtained from whole blood samples collected without antiserum. PBMCs were isolated from blood using ethylenediaminetetraacetic acid (EDTA)-coated tubes. The lymphocyte separation media  was used to isolate PBMCs from blood following the manufacturer’s instructions.Myocardial biopsies were obtained from the atrium of ischaemic patients with heart failure (HF) during cardiac surgery. The 7 HF patients  had a median age of 62 years, and their ejection fraction (EF) before surgery was 52% ± 12%. Fully informed written consent was obtained from the families of all donors.Blood samples were collected before the start of the PPCI procedure and at multiple time points following PPCI. We used the miRNeasy Serum/Plasma kit  to extract small RNAs from serum. Briefly, 200 μL of serum was mixed with 700 μL of QIAzol Lysis Reagent included in the kit, and 10 pmol of Arabidopsis miRNA (ath-miR-159a) was added as a spike-in control. Then, we followed the manufacturer’s instructions to obtain the fraction of eluted miRNAs. To obtain small RNAs from PBMCs, we used the mirVana miRNA Isolation Kit . The eluted miRNAs were quantified using a fluorometer  through a Qubit miRNA assay . We used TaqMan array miRNA card pool A  to examine miRNA expression in 9 STEMI and 3 control patients. Once we had selected miRNA candidates, custom TaqMan miRNA arrays  were designed to amplify miRNAs. To validate miRNA expression, we used RT-qPCR using the TaqMan Advanced miRNA cDNA Synthesis Kit, TaqMan Advanced miRNA Assay, and TaqMan Fast Advanced Master Mix technology. To determine miRNA expression in PBMCs, we used the miScript II RT Kit  and iTaq Universal SYBR Green Supermix . RT-qPCR was performed using an Applied Biosystems Viia7 7900HT thermocycler. Relative quantification analyses were performed using the software SDS2.2 and Expression Suite Software V1.0.3 , online software ThermoFisher Cloud and QuantStudio Real Time PCR Software  and Excel. Fold changes in miRNA expression were calculated using the comparative cycle threshold CT (ΔΔCT) method. The values are expressed as the logarithm of the fold change.http://mirdb.org, Washington University St. Louis, MO, USA) and TargetScan  databases to analyse miRNA targets. We found common targets between the databases through a Venn diagram. To identify microRNA target gene pathways, we used an online platform from the Gene Ontology (GO) browser PANTHER . We used the miRDB  and the appearance of LVAR. LVAR was taken as the binary dependent variable, miR-320a expression as the independent, and CK, sex and age as the covariates for adjustment. Linear regression analysis was conducted using the percentage of change in LVEDV as dependent variable. The LVAR predictive value of different parameters  was also evaluated using the receiver operating characteristic (ROC) curve.Data were analysed using SPSS  and with GraphPad . The results are presented as the mean and standard error of the mean (SEM). The outliers were removed based on the results of QuickCalcs, an online tool of GraphPad. The Shapiro–Wilk test was used for normality. For normally distributed variables, we used an ordinary one-way ANOVA, and we performed multiple comparisons using T-test without correction (Fisher’s LSD test). For non-normal distribution, we used the non-parametric Kruskal–Wallis test with multiple comparisons corrected by Dunn’s test. Multivariate logistic regression analysis was performed to estimate the independent relationship between variables with significant differences (p > 0.05) in terms of age, risk factors and LVEDV index at the time of admission. In contrast, we observed significant differences in cardiac markers, creatine kinase and troponin T between both groups at the onset of PPCI.Clinical information about the study subjects is shown in Samples from control and STEMI patients with TIMI 0 flow were used to detect the profiles of miRNAs secreted in the serum 3 to 6 h after PPCI by a RT-qPCR-based array. We also examined the levels of other miRNAs , selected based on a literature search focusing on their relevance in different CVD ,32,33,34p > 0.05).To further characterize the relevance of the observed changes in the expression of miRNAs, we examined whether their levels were different in patients who developed LVAR 6 months after PPCI compared to those who did not present any adverse events after PPCI interventions. n = 8) with or without LVAR (n = 8). n = 39). In this case, we considered 6 h as the optimal time point to test the miRNA maximum levels after PPCI, and we also evaluated its expression 1 month after revascularization. Next, based on our previous results, we compared the expression of miR-320a, miR-193b, miR-324, miR-339-5p, miR-519a, miR-522, and miR-545 in STEMI patients (p = 0.03) correlated inversely and significantly with the percentage of changes in LVEDV, meanwhile CK  and age  showed worse association with LVEDV changes. Moreover, ROC curve analysis in p value = 0.004), while the AUC of CK was 0.722 , and of age was 0.530  (p < 0.045).Linear regression and ROC analysis were performed to further confirm that changes in circulating levels of miR-320a associates with LVAR. = 0.819) . ROC anaP = 0.071 at 6 h, and OR, 0.206; 95% CI, 0.037–1.140; P = 0.070 at 1 month post PPCI).Since AMI involves a complex cascade of events that activate acute inflammatory responses , we examn = 7). As illustrated in Finally, we examined the expression of miR-320a and other miRNAs in patients with HF of ischaemic origin. http://pantherdb.org/genelistanalysis.do, University of Southern California, Los Angeles, CA, USA), we generated a graphic showing that 1060 genes and 520 pathways were mainly implicated in the processes regulating adverse remodelling  miRNAs are quickly released into the circulation in different patterns following successful coronary artery revascularization in STEMI patients; (ii) a rapid increase in circulating miR-320a was observed in STEMI patients; (iii) circulating miR-320a decrease 1 month post PPCI correlates with the appearance of LVAR; (iv) the levels of miR-320a in PBMCs correlates inversely with expression in blood; and (v) higher expression of miR-320a is detected in the heart tissue of patients with HF of ischaemic origin.In recent years, circulating miRNAs in patients with myocardial infarction have been extensively studied ,25,39. FRecent studies on the use of PPCI described that miRNAs might also predict worse outcomes of patients who underwent PPCI. For example, miR-1 and miR-133b levels increased within 3 h of PPCI, and these miRNAs are positively associated with microvasculature obstruction and worse left ventricular functional recovery . miR-125To identify the putative source of this fast increase in the level of miR-320a, we examined its expression in PBMCs since these cells have been implicated in the early inflammatory process (as reviewed elsewhere ). Our daThis study shows detailed miRNA release kinetics in the initial hours following PPCI. This analysis provides evidence for miR-320a as a potential prognostic biomarker for LVAR in patients who have undergone PPCI, which is promising for the preventive treatment of clinical heart failure. Further studies are needed to establish the pathophysiological and clinical significance of increased circulating miRNA-320a levels and to investigate the therapeutic efficacy of targeting miRNA-320a.The present study aimed to validate the proof-of-concept that circulating miRNAs can predict the outcome of STEMI patients undergoing PPCI.In evaluating the results of this study, one must take several limitations into account:The small sample size used in this study, due to the difficulty of recruiting patients with homogeneous criteria. Patients are only from two hospitals, therefore, a large-scale and multicentre study would be welcomed to confirm the role of miRNA-320a as a potential biomarker for STEMI patients with LVAR.The results are limited only to patients with early revascularized STEMI with TIMI flow 0.Our findings are essentially limited to a change in the volume of the left ventricle after revascularized STEMI up to six months, and remodelling may increase afterwards.The specific roles of miRNAs have not been evaluated in terms of the ability to regulate gene expression in human cardiac myocytes.It is possible that other miRNAs may also have prognostic value in this context, since RNA sequencing or microarray approaches are continuously improving in terms of sensitivity and specificity.


Allogeneic hematopoietic cell transplantation (HCT) remains the only curative therapy for many hematological malignant and non-malignant disorders. However, key obstacles to the success of HCT include graft-versus-host disease (GVHD) and disease relapse due to absence of graft-versus-tumor (GVT) effect. Over the last decade, advances in “omics” technologies and systems biology analysis, have allowed for the discovery and validation of blood biomarkers that can be used as diagnostic test and prognostic test (that risk-stratify patients before disease occurrence) for acute and chronic GVHD and recently GVT. There are also predictive biomarkers that categorize patients based on their likely to respond to therapy. Newer mathematical analysis such as machine learning is able to identify different predictors of GVHD using clinical characteristics pre-transplant and possibly in the future combined with other biomarkers. Biomarkers are not only useful to identify patients with higher risk of disease progression, but also help guide treatment decisions and/or provide a basis for specific therapeutic interventions. This review summarizes biomarkers definition, omics technologies, acute, chronic GVHD and GVT biomarkers currently used in clinic or with potential as targets for existing or new drugs focusing on novel published work. Allogeneic hematopoietic cell transplantation  remains the most widely used immunotherapy for the treatment of many hematologic disorders. While HCT induces beneficial graft-versus-tumor (GVT), the development of graft-versus-host-disease (GVHD) remains a major cause of mortality and morbidity in patients post-HCT. There are two main clinical presentations of GVHD: acute GVHD (aGVHD) and chronic GVHD (cGVHD). aGVHD affects up to 50% of allo-HCT recipients, and is characterized by an exacerbated inflammatory response and a combination of signs and symptoms that target the skin, liver and the gastrointestinal track. The clinical manifestation of aGVHD includes nausea, vomiting, anorexia, watery or bloody diarrhea with crampy abdominal pain, maculopapular rash, and cholestatic liver disease , 2. On tOver the years, advances in bioinformatics including machine learning, chemistry, engineering, and high-throughput technical instruments have massively contributed to the development of “omics” technologies. Using these tools, several novel specific and sensitive blood based-biomarkers were identified and validated in large patient’s cohort to aid in the diagnosis, prognosis, risk prediction, and response to therapy of patients post-HCT. These biomarkers can serve as potential therapeutic targets for existing or novel drugs and also be exploited to facilitate with the diagnosis and clinical assessment of disease severity in patients to enable an optimal clinical management during disease progression.This review will summarize these novel drug-targetable aGVHD, cGVHD and GVT biomarkers post-HCT identified using a large number of patients (cutoff of at 50 patients per cohort), a validation cohort, and validated at the protein level with the potential for rapid translation into the clinic.The Working group on biomarkers for the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host disease (GVHD) report and the North American and European Consortium put forward a list of definitions for GVHD biomarkers , 8. A bi(1)A diagnostic biomarker is used to identify GVHD patients at the onset of the disease and aid to differentiate their symptoms from other conditions.(2)A prognostic biomarker is used to identify patients with different degree of risk for GVHD occurrence, progression or resolution before the onset the disease.(3)A predictive biomarker categorizes patients based on their likelihood to respond to therapy before GVHD therapy.(4)A response to treatment biomarker aids monitor patients’ response to treatment when pre-therapy sample is collected.The development of biomarkers is complex and consists of multiple phases, from candidate molecular targets to routine use in the clinics. Prior to prospective studies, validation with both training and verification cohorts, then validation in independent cohorts must be conducted , 8. The x-axis versus 1 minus sensitivity on the y-axis for every possible cut off  reducing peri-transplantation risk and (2) facilitating diagnosis and prognosis of HCT-related complications. Gene signatures were previously associated with GVHD prevention and management. Single chain polymorphism (SNPs) are the most common types of naturally occurring mutations in a population. In a retrospective study, a total of 25 SNPs in 12 cytokine genes were evaluated in a cohort of 509 HLA-identical sibling donor allo-HCT patients for the prediction of aGVHD and cGVHD. Using a linear regression model and the least absolute shrinkage and selection operator (LASSO), SNPs combined with other clinical factors could predict severe GVHD . AnotherDue to the complexity of data analysis and data acquisition, the use of proteomics analysis is mostly limited to specialized laboratories. Yet, the main advantage is that biomarkers discovered through proteomics actually indicate the state of the disease. GVHD biomarkers have been discovered using proteomics analysis. Antibody arrays are quantitative and highly sensitive for the detection of low-abundance proteins such as cytokines. Their main limitation is the restricted number of antibodies on the array, thus affecting the discovery of candidate biomarkers. Another powerful tool for qualitative and quantitative discovery of proteins in a complex protein mixture is next generation mass spectrometry (MS), which uses a gel-free separation method for the first step most likely liquid chromatography, followed by MS. MS, particularly tandem MS uses label-free methods or isotopically labeled tags for non-ambiguous quantification. Proteins are identified from a mass spectra matched to a sequence database . AlthougDespite the great promise for biomarker discovery using next-generation MS, they are limitations between biomarker validation and discovery due to (1) the paucity of affinity-capture reagents that has led to bias in the prioritization of candidate biomarkers, and (2) the increase in the number of samples necessary for validation that augments when a biomarker passes to each test phase, thus creating the need for high-throughput assays. Sandwich enzyme linked immunosorbent assay (ELISA) is the most specific and reliable approach for the quantification of individual proteins because this method is simple, very easy to perform with high reproducibly .+CD146+CCR5+ T cells in aGVHD or cGVHD, and the blood mucosal-associated T cells , without significant spillover between channels. Although CYTOF is limited to the markers used, this technology and its software have enabled the discovery of new cell populations such as regulatory T cells (Tregs) –22, B cein cGVHD –30. Althin cGVHD .+ T cells in NHP and CD4+ and CD8+ T cells in humans in both supervised and unsupervised gene expression analyses for the identification of pathways controlling GVHD, and discovered three transcriptional hallmarks of breakthrough aGVHD that are not observed in hyperacute GVHD: (1) T cell persistence rather than proliferation, (2) a highly inflammatory programming, (3) a T helper (Th)/Tc1-mediated dysfunction driven by inflammatory IL-17 dominated pathways   high Reg3α levels at day 56 predict the development of chronic GVHD, demonstrating that machine learning can be utilized to demonstrate the association of immune cell subsets and biomarkers with outcomes after HCT  . Using t< 0.001) . Further< 0.001) . This ty< 0.001) . Another< 0.001) . More refter HCT . MachineOver the years, several biomarkers have been discovered and validated in both aGVHD and cGVHD. According to the NIH consensus on biomarkers, some proteins were moved from candidate proteins to biomarkers . Those vScreening of aGVHD plasma samples using antibody microarrays for 120 proteins and ELISA enabled for the discovery and validation of the first panel of biomarkers consisting of a 4-protein biomarker panel: IL-2Rα, TNFR-1, IL-8, and HGF. This panel of biomarkers can confirm the diagnosis of aGVHD in patients, and COX regression analysis revealed that the panel can also predict survival independent of GVHD severity .Interleukin-6 was identified as a predictive biomarker for severe GVHD and NRM at both days 3 and 60 post-transplant in a cohort of 53 HCT patients. This finding was then validated in a second cohort, where IL-6 was elevated at the onset of GVHD .p < 0.001  either measured alone or with other markers. (1) ST2 serves as a predictive biomarker. ST2 was first identified in plasma obtained at a median of 16 days after the initiation of aGVHD therapy in 10 patients with a complete response by day 28 post-therapy initiation and compared to 10 patients with progressive aGVHD during therapy. In that study, 12 biomarkers were compared, and ST2 showed the highest association with resistance to aGVHD and death without relapse. Patients with high ST2 levels had a higher risk to develop treatment resistant-aGVHD compared to patients with low ST2 levels . Additio < 0.001 . In a th < 0.001 . We note < 0.001 , cord bl < 0.001 , HCT pos < 0.001 . In a co= 0.0056 . (3) Las= 0.0056 . Similar= 0.0056 , 65.The role of angiogenic factors in late aGVHD was tested by comparing controls and cases aGVHD patients in a cohort of 105 patients, then validated in a cohort of 37 cases. The authors found that AREG-to-EGF ratio at or above median was associated with lower overall survival and higher NRM in both cohorts. AREG-to-EGF ratio was also elevated in classic aGVHD, but not in cGVHD . This fiCertain biomarkers are organ specific and enable the distinction for instance from skin rashes and skin GVHD, or other forms of enteritis to GI-GVHD. Target-specific aGVHD biomarkers are:Elafin was also discovered using next-generation proteomics and validated as both a diagnostic and prognostic biomarker for skin GVHD, which is associated with GVHD severity and NRM , 68.Regenerating islet-derived 3-α, HGF, and KRT18 were elevated in patients with liver GVHD in a cohort of 954 patients from three centers. It is important to note that REG3α had a better AUC for the diagnosis of liver GVHD than HGF and KRT18. However, this panel of liver GVHD specific biomarker was not validated due to the low incidence of liver GVHD , 70.T-cell immunoglobulin mucin-3 and Reg3α are GI-GVHD specific biomarkers that were identified and validated as prognostic biomarkers that can identify patients at high risk for lethal aGVHD at day 7 and day 14 for each, respectively , 59. Usi+CD25hiFoxp3+ Tregs showed both a diagnostic and predictive value as a biomarker for aGVHD. Lower Tregs in the peripheral blood of patients was associated with the development of aGVHD. Furthermore, patients with Tregs frequencies lower than the median exhibited higher NRM compared to patients with Tregs higher than the median  as well as late cGVHD (≥9 months) –95. sBAFA biomarker panel consisting of ST2, CXCL9, MMP-3, and osteopontin was significantly correlated with cGVHD. Furthermore, when measured at diagnosis or at day + 100 post-transplantation, this panel allowed for patient risk stratification according to cGVHD risk . MMP-3 wUsing a tandem mass spectrometry proteomics analysis using a multiorgan cGVHD model, CCL15, the human homolog of CCL9, was identified as a novel cGVHD biomarker in a cohort of 211 patients. In addition, patients with higher than median levels of CCL15 showed a higher risk of NRM, demonstrating that biomarkers identified through murine proteomics can also enable for the discovery of novel biomarkers in patients .de novo onset of cGVHD. Patients with plasma soluble CD163 concentration at day 80 had a cumulative incidence of de novo-onset of cGVHD of 75% vs. 40%, p = 0.018, in patients with lower concentration of CD163  expressing B cells have been associated with the development of cGVHD in patients post-transplantation . Immaturof cGVHD , 103. Laof cGVHD .+CD25+T cells in patients with cGVHD compared to patients without cGVHD (p = 0.009)  . In anot= 0.009) .+ CD146+ CCR5+ T cells, a TH-17 prone subset of CD4+ T cells was highly expressed in cGVHD patients and sensitive to pharmacological inhibition. In a murine model, donor T cells obtained from CD146-deficient mice had significantly reduced pulmonary cGVHD compared to the wild-type mice. Moreover, the CD146-deficient mice had significantly lower pulmonary macrophage infiltration and T cell CCR5, IL-17, and IFN-γ coexpression (A novel subset of CD4pression .Lower circulating TFH (cTFH) cells have been found in patients with active cGVHD compared to patients without cGHVD. Findings also demonstrated that cTFH are activated and exhibit a Th2/Th17 phenotype that promotes B-cell help function during cGVHD .In tumor immunotherapy, allo-HCT with donor lymphocyte injection (DLI) promotes tumor cell killing through the GVT effect. However, often times, the GVT effect is limited by the development of aGVHD. Therefore, plasma biomarkers that can distinguish GVT without GVHD would be beneficial. Recently, plasma proteomics and systems biology analyses were conducted on patients who experienced GVT and aGVHD compared to the proteome of patients who experienced GVT without aGVHD. The authors identified a total of 76 proteins that were associated with GVT without GVHD. Additionally, an unique 61-protein signature was also identified in patients with GVT without GVHD. 43 genes of the 61 genes in the protein signature were further confirmed using single-cell RNA sequencing analysis. More importantly, few potential GVT biomarkers such as RPL23, ILF2, CD58, and CRTAM were identified in GVT without GVHD . These G+ Tregs  cells and ST2+ Tregs . REG3α i+ Tregs .+ cells such as Tregs, IL-9-expressing T cells, and innate lymphoid cells showed the same effect. This is currently being evaluated in clinical trials  inhibitors either directly or via intracellular signaling . This isl trials , 112.Many specific and sensitive biomarkers for both aGVHD and cGVHD have been identified over the past decades. While these biomarkers can be exploited for patient-risk stratification, early GVHD assessment, monitoring of GVHD progression and for cost-effective management decision-making, no biomarkers are widely used in clinic. One of the main limitations for the application of biomarkers in clinics has been the lack of an adequate number of multicenter clinical trials. All candidate biomarkers require to be thoroughly validated from preclinical investigation to independent clinical research in large multicenter cohort setting(s) . In addiAdvances in technology in the field of omics have permitted the discovery of numerous biomarkers for identification of complications post-HCT and signature of the beneficial GVT. A good biomarker has several features: has been developed through the different phases including discovery and validation in large independent cohorts, use a cost efficient non-invasive robust assay that has been qualified. If, in addition the biomarker is mechanistic, the likelihood of this biomarker to be relevant is increased as for example ST2 that has been shown to be secreted by IFNγ producing T cells. If the biomarker is involved in the pathogenesis of the disease, it is likely that drugs  could target the pathway involved. Future directions should include aGVHD biomarkers preemptive trials. Biomarkers for other diseases such as autoimmunity should follow the same criteria.DA and SP devised and wrote the manuscript. All authors contributed to critical revisions of the manuscript.SP is an inventor on a patent on “Methods of detection of graft-versus-host disease” . KRC is on the advisory board of Jazz pharmaceuticals. CRYC is co-founder of Mana Therapeutics.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There is paucity of data on optimal medical treatment, including use of beta blockers for patients undergoing transcatheter aortic valve replacement (TAVR). The study aimed to investigate the association of beta blockers and clinical outcomes following TAVR.We examined data of 2563 patients who underwent TAVR between October 2013 and May 2017 obtained from a prospective multicentre cohort registry, the optimised catheter valvular intervention-TAVI registry. We compared the 2-year cardiovascular and non-cardiovascular mortality and in-hospital outcomes between patients with and without preprocedural beta-blocker administration by propensity score matching (PSM).Preprocedural beta blockers were prescribed in 867 patients (33.8%). After PSM, the incidence of in-hospital congestive heart failure was significantly lower in patients with preprocedural beta blocker (p=0.046). No differences were found in 2-year cardiovascular and non-cardiovascular mortality. In the subgroup analyses, beta-blocker administration was associated with a lower cardiovascular mortality within 2 years in patients with a history of coronary artery bypass grafting , presence of peripheral artery disease  and brain natriuretic peptide (BNP) ≥400 pg/mL (log-rank p=0.003). When stratified by postprocedural left ventricular ejection fraction (post-LVEF), beta-blocker administration was associated with a lower cardiovascular mortality among patients with post-LVEF <50% (log-rank p=0.024).Preprocedural beta-blocker administration was not associated with 2-year cardiovascular and non-cardiovascular mortality in overall, but was associated with a lower 2-year cardiovascular mortality in patients with a history of CABG, presence of PAD, BNP ≥400 pg/mL and post-LVEF <50%. The findings must be validated using randomised trials. Transcatheter aortic valve replacement (TAVR) is an established therapy for symptomatic patients with severe aortic stenosis. However, the optimal medical therapy, including beta blockers for patients who undergo TAVR, remains unspecified.The study showed that beta-blocker administration was associated with a lower 2-year cardiovascular mortality in patients with a history of coronary artery bypass grafting , presence of peripheral artery disease , brain natriuretic peptide (BNP) ≥400 pg/mL and postprocedural left ventricular ejection fraction (LVEF) <50% (log-rank p=0.024).This result suggests that beta-blocker administration was associated with good clinical outcomes among patients with a history of CABG, presence of PAD, BNP ≥400 pg/mL and post-procedural LVEF <50%. The findings need to be confirmed by randomised trials.It is not clear whether medical therapy is advantageous for the treatment of aortic stenosis (AS). Several prior studies have shown that renin–angiotensin system (RAS) inhibitors for AS are associated with improved survival.4Transcatheter aortic valve replacement (TAVR) is an established therapy in patients with symptomatic severe AS at high or intermediate surgical risk.A total of 2588 patients were enrolled in the Optimised transCathEter vAlvular iNtervention (OCEAN)-transcatheter aortic valve implantation (TAVI) registry between October 2013 and May 2017. The OCEAN-TAVI registry is a prospective, multicentre, observational registry of patients who underwent TAVR using the Edwards Sapien XT/Sapien 3 prosthesis  or Medtronic Corevalve/Evolut R prosthesis  at 14 Japanese medical centres. All study participants provided informed consent and the registry was approved by the ethics committees of all participating institutions. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research. The OCEAN-TAVI registry was registered with the University Hospital Medical Information Network Clinical Trial Registry and accepted by the International Committee of Medical Journal Editors (UMIN-ID: 000020423). Patients were followed annually at the participating institutions. At that time, blood tests, echocardiography were performed. The events were site reported from the participating institutions and not adjudicated in clinical event adjudication committee. The database was regularly audited by the data committee members to ensure the consistency.After exclusion of 25 patients owing to conversion to open surgery, 2563 patients participated in this study and were divided based on whether or not they were administered preprocedural beta blockers . PreprocThe primary outcomes were 2-year cardiovascular and non-cardiovascular mortalities after TAVR. For patients who lost to follow-up, we used the last date when survival was confirmed. The secondary outcomes were as follows: in-hospital outcomes and complications and postprocedural echocardiographic data. Cardiovascular mortality and complications were defined based on the Valve Academic Research Consortium (VARC)-2 criteria.2/m2 according to the VARC-2 criteria.Transthoracic echocardiography was performed at baseline, before hospital discharge, and at the annual follow-up. All transthoracic echocardiographic parameters were measured according to the guidelines of the American Society of Echocardiography.2 test or Fisher’s exact test.We compared baseline characteristics between patients with and without preprocedural administration of beta blockers . ContinuBaseline variables are listed in 10.1136/openhrt-2020-001269.supp1Supplementary dataCumulative incidences were calculated using the Kaplan-Meier method in the matched cohort. The log-rank test was performed to compare cardiovascular mortality between patients with and without preprocedural administration of beta blockers.To identify the groups for which beta blockers were effective, subgroup analyses for cardiovascular mortality were performed for age (≥80 or <80 years), sex, chronic kidney disease (CKD), atrial fibrillation (AF), coronary artery disease (CAD), coronary artery bypass grafting (CABG), peripheral artery disease (PAD), preprocedural left ventricular ejection fraction , preprocedural aortic regurgitation , preprocedural mitral regurgitation  and brain natriuretic peptide . In subgroup analyses for cardiovascular mortality, patients with BNP 2 or <20 kg/m2), New York Heart Association (NYHA) class , CKD, PAD, chronic obstructive pulmonary disease (COPD), albumin levels (≥3.5 g/dL or <3.5 g/dL) and clinical frail score . Interaction tests between each covariate were performed. PSM after multiple imputation was performed in the subgroups with p for interaction <0.05. We selected the subgroup from the original data including 2563 patients, then performed PSM for preprocedural beta blockers because the baseline characteristic between beta-blocker group and non-beta-blocker group would be consistent in the subgroup. The log-rank test was performed to evaluate cardiovascular mortality between patients with and without preprocedural beta-blocker administration in the subgroups.To confirm the safety of beta blockers for patients undergoing TAVR, subgroup analyses for non-cardiovascular mortality were performed for age (≥80 or <80 years), sex, body mass index , the postprocedural LVEF . PSM for preprocedural beta-blocker administration was performed in each group. The log-rank test was performed to evaluate cardiovascular mortality.All statistical analyses were performed using SPSS V.23.0  and R software V.3.5.2 . All tests were two sided and statistical significance was set at p<0.05.The baseline characteristics of the study participants are shown in A total of 1558 patients were matched . After pKaplan-Meier curves of cardiovascular and non-cardiovascular mortality in the non-matched and matched cohort are shown in Regarding the matched cohort, in-hospital patient outcomes, complications and postprocedural echocardiographic data are shown in Subgroup analyses for cardiovascular mortality are shown in Subgroup analyses for non-cardiovascular mortality are shown in Kaplan-Meier curves of cardiovascular mortality in each group ,20et al reported that beta-blocker discontinuation was associated with an increased risk of high degree AV block or AF among patients with TAVR.21Two remaining and frequent complications of TAVR are PVL and pacemaker implantation. Administration of beta blockers is considered harmful in patients with AR because of a longer diastolic period. Additionally, beta blockers suppress atrioventricular conduction. Therefore, there was concern that beta-blocker administration would increase the risk and impact of these complications. However, there was no significant difference in PVL degree and new permanent pacemaker implantation rate between patients with and without beta-blocker administration in this study. On the contrary, Younis In this study, beta blockers were associated with a lowered non-cardiovascular mortality in patients with COPD. It was assumed that beta blockers were contraindicated in patients with COPD because of potential exacerbation. Recently, beta-blocker use in patients with COPD was associated with decrease in all-cause mortality and exacerbation rate.et al reported that there was no clear evidence of the prevention of beta blockers on congestive heart failure after cardiac surgery.Blessberger et al reported that the lesion of CAD in patients with PAD was often more severe than that in patients without PAD.17–19 29 30All specific groups identified in this study are at high risk of heart failure or cardiovascular event. Patients undergoing TAVR with a history of CABG, presence of PAD, high BNP levels or LVEF <50% had high mortality rates.In this study, there was no association between the presence and absence of beta-blocker administration in cardiovascular mortality in patients with pre-LVEF <50% or In this study, we found that beta blockers were not associated with the risk of increased complications and non-cardiovascular mortality. Additionally, we identified the association with beta blockers and clinical outcomes. The optimal medical therapy for patients who undergo TAVR would be important because the indications for TAVR are expanding and the number of these patients is increasing. However, this study could not identify the doses and types of beta blockers. Prospective studies are needed to evaluate these issues.This study has several limitations. First, it was a non-randomised, retrospective study using data from a prospective multicentre cohort registry including a limited number of patients; however, this cohort is representative of real-world practice. Further studies with a larger number of patients are ongoing. Second, the definition of in-hospital congestive heart failure is unique to this registry. Additionally, no information was available on the amounts, types of infusion or drugs used during the procedure that may affect the onset of congestive heart failure. The result of low incidence of in-hospital congestive heart failure is beyond the scope of the effect of beta blockers because the definition includes mechanical support for heart failure, such as IABP and ECMO. In addition, inotropic agents and mechanical support were also used not only for heart failure but also for the cardiogenic shock management. In-hospital congestive heart failure did not include the cases in which inotropic agents or mechanical support was used for other than heart failure. However, the reasons for the use of inotropic agents or mechanical support were site reported from the participating institutions. The diagnosis of heart failure was left to the discretion of the clinicians in each participating institution. Third, no information regarding the dose or period of administration, time schedule or type of beta blockers was included. There was not enough information of medication status at follow-up. In randomised controlled trials, carvedilol, bisoprolol or metoprolol succinate reduce all-cause mortality in patients with HFrEF.Preprocedural beta-blocker administration for patients undergoing TAVR was not associated with 2-year cardiovascular and non-cardiovascular mortality in overall, but was associated with a lower risk of 2-year cardiovascular mortality only in patients with a history of CABG, presence of PAD, BNP


The COVID-19 pandemic is ongoing, yet, due to the lack of a COVID-19-specific tool, clinicians must use pre-existing illness severity scores for initial prognostication. However, the validity of such scores in COVID-19 is unknown.The North West Collaborative Organisation for Respiratory Research performed a multicentre prospective evaluation of adult patients admitted to the hospital with confirmed COVID-19 during a 2-week period in April 2020. Clinical variables measured as part of usual care at presentation to the hospital were recorded, including the Confusion, Urea, Respiratory Rate, Blood Pressure and Age Above or Below 65 Years (CURB-65), National Early Warning Score 2 (NEWS2) and Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) scores. The primary outcome of interest was 30-day mortality.Data were collected for 830 people with COVID-19 admitted across seven hospitals. By 30 days, a total of 300 (36.1%) had died and 142 (17.1%) had been in the intensive care unit. All scores underestimated mortality compared with pre-COVID-19 cohorts, and overall prognostic performance was generally poor. Among the ‘low-risk’ categories , 30-day mortality was 16.7%, 32.9% and 21.4%, respectively. NEWS2≥5 had a negative predictive value of 98% for early mortality. Multivariable logistic regression identified features of respiratory compromise rather than circulatory collapse as most relevant prognostic variables.In the setting of COVID-19, existing prognostic scores underestimated risk. The design of new prognostic tools should focus on features of respiratory compromise rather than circulatory collapse. We provide a baseline set of variables which are relevant to COVID-19 outcomes and may be used as a basis for developing a bespoke COVID-19 prognostication tool. The novel coronavirus SARS-CoV-2 is causing a global pandemic of the infectious disease termed COVID-19. COVID-19 is frequently associated with a pneumonia syndrome and the large ISARIC  observational study estimates a case fatality rate of 33% among those admitted to hospital.The Confusion, Urea, Respiratory Rate, Blood Pressure and Age Above or Below 65 Years (CURB-65) score is a community-acquired pneumonia (CAP)-specific tool for predicting all-cause mortality within 30 days. CURB-65 has been validated across large, diverse patient populations and has been endorsed by national and international guidelines as an aid to clinical decision making.At the onset of the UK epidemic, in the absence of COVID-19-specific prognostic tools, CURB-65, NEWS2 and qSOFA remained in widespread use, but little was known about their validity in the COVID-19 setting. The primary aim of this study was to determine the performance characteristics of these scores in the context of COVID-19 and, secondarily, to investigate potential components of a COVID-19-specific prognostication tool for future validation.https://www.hra.nhs.uk/covid-19-research/guidance-using-patient-data/).The North West Collaborative Organisation for Respiratory Research (NW-CORR) collected data during the 2-week period from 1 April 2020 to 14 April 2020 on prospective adult COVID-19 admissions at seven acute hospitals in North West England. NW-CORR constitutes a group of research-interested, respiratory, specialist trainee grade doctors, and the recruiting centres were those with an NW-CORR member available. Collaborators were asked to record routinely collected clinical data for consecutive patients admitted to their hospitals who met the Public Health England inpatient case definition for COVID-19Healthcare professionals with COVID-19 were involved in the design, conception and conduct of the study. All agreed the project was desirable and non-intrusive for patients and deliverable during a time of crisis.Data collected included demographic characteristics, vital signs and blood test results. All physiological values and blood results constituting components of the CURB-65, NEWS2 and qSOFA scores were the earliest measurement recorded in the hospital. The variables included in each risk score are shown in Anonymised study data were collated centrally and managed using the secure, web-based software platform Research Electronic Data Capture  hosted at the University of Liverpool. In general, there were minimal missing data with >99% completeness for all constituent variables of the three prognostic scores .Scores were assessed individually against their validated outcomes and overall for their ability to identify people at risk of mortality within 72 hours (early death) and 30 days of admission. This analysis included sensitivity and specificity of each score’s respective risk strata followed by an evaluation of discrimination and calibration in keeping with TRIPOD guidelines.Multiple logistic regression models were fitted for each of the outcome variables  using each score . With the aim of identifying variables relevant to COVID-19 outcomes and in order to assess the association of each individual variable  with each of the outcomes, multiple regression modelling using all variables was fitted by applying backward variable selection. Data heterogeneity introduced by differences among hospitals was assessed by adding a random intercept in the model. However, clustering by hospital did not improve the accuracy of the model, and the final models did not include a random term. The performance of the fitted models was assessed by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and AUC. These analyses were performed using the statistical software package pROC in R V.3.5.3. pROC features internal cross validation based on bootstrap sampling method.Data were collected and recorded for 830 patients admitted to seven hospitals in the North West of England, encompassing both secondary and tertiary care hospitals see  material10.1136/bmjresp-2020-000729.supp1Supplementary dataThe discriminatory ability of each score was assessed for death within 30 days, death within 72 hours and admission to critical care, and are presented in To test scores’ performance at their individual validated thresholds, the sensitivity, specificity, NPV and PPV were calculated for patients with complete datasets see  and are 2) and respiratory rate strata were relevant to mortality (OR 2.00 (1.4–2.8), p<0.001 and OR 1.9 (1.3–2.9), p=0.003, respectively).When all individual variables were considered, multivariable logistic regression revealed that confusion and blood pressure (BP) were less relevant to 30-day mortality than urea, respiratory rate and age when computed as part of the CURB-65 score see . In a si2, Sex, Respiratory rate (CUCAF-SR)) and a similar set of variables for 72-hour mortality ), as shown in Finally, a backward selection multivariable model fitted for each outcome identified de novo a set of variables independently associated with 30-day mortality  showed excellent NPV. We went on to derive two sets of parameters which, when combined on admission with COVID-19, may provide a more accurate prediction of mortality and may provide a useful basis for predictive scores to be validated in larger datasets.CURB-65 was derived and validated to predict low, moderate and high risk of death at 30 days in patients with CAP and therefore assisted healthcare workers in deciding who required admission to the hospital. Pre-COVID validation demonstrated a score of <2 was consistently associated with low mortality rates of 0.4%–2.8% at 30 days.In the pre-COVID era, at the time of presentation to hospital with CAP, it was extremely unusual for the medical team to know the causal pathogen, and although it was well recognised that there was a range of virulence among the possible viral and bacterial causes of CAP, the data presented here confirm that SARS-CoV-2 is a highly virulent outlier. This finding has particular relevance to the evolving pandemic since, as transmission reduces, SARS-CoV-2 will become one of numerous endemic causes of CAP in many countries. It will therefore be important to recognise that this will reduce the performance of CURB-65 on undifferentiated CAP cases and makes a strong case for the implementation of rapid diagnostics to determine the aetiology of CAP.NEWS2 has been widely implemented in English hospitals as a simple score consisting of routine physiological measurements. While it is most widely recognised as a simple tool to identify inpatients in need of urgent or emergent medical attention based on changing physiological measurements, it is also often used in the emergency department, where it has been validated in a number of syndromes, including sepsis and acute dyspnoea.qSOFA was validated for use among hospital inpatients and emergency department admissions as a simple and accurate way to identify people with infections at higher risk of poor outcomes.The poor performance of qSOFA is interesting, given it was derived from cohorts of patients with sepsis, a syndrome defined as a ‘life-threatening organ dysfunction due to a dysregulated host response to infection’. It would be expected that many with COVID-19-associated mortality would meet that definition on the basis of respiratory failure. However, the striking difference between the physiology of bacterial sepsis and severe COVID-19 is that cardiovascular instability is rare in COVID-19.Blood pressure and mental status are integral components of the qSOFA score and in other contexts contribute to its ability to prognosticate; thus, the poor performance of qSOFA is explained by the limited effect of COVID-19 on these physiological parameters. These findings suggest COVID-19-associated mortality may be mediated by different mechanisms than conventional bacterial sepsis. An example of this may be the profound endothelial injury and abundant microthrombi identified in a recent postmortem study.Given the limited performance of the previously validated and widely used scores seen here, we explored whether performance could be improved by deriving new models. Using multiple logistic regression, we derived new models, CUCAF-SR and CUCA-SF, in an attempt to predict 30-day and 72-hour mortality, respectively. In keeping with the findings described earlier, markers of cardiovascular compromise were not independently associated with poorer outcomes, with markers of respiratory function, age and frailty appearing more relevant. This finding is supported by the findings of the ISARIC study, where respiratory function (respiratory rate and oxygen saturations), age and comorbidities, but not cardiovascular parameters, were important constituents of the 4C mortality score.Some limitations must be addressed. First, we only included a 2-week period, and it is possible demographics and outcomes may change across the course of the COVID-19 pandemic.A further limitation here is the inclusion only of those people admitted to hospital, thus excluding those well enough to be discharged from the emergency department. As a consequence, the observed risk presented among low-risk categories seen here may, in theory, be inflated; for example, it is possible only the sickest patients with CURB-65 scores of 0–1 were admitted. However, the main derivation dataset for the CURB-65 score included only patients admitted to the hospital, replicating the methods here.The strengths of this study lie in the prospective collection of data on consecutive admissions from multiple regional hospitals with rigorous assessment of the performance of each score. These readily available data were compiled from real-world clinical assessment, and outcomes followed usual clinical care. We also demonstrate the hitherto underappreciated potential of highly trained and motivated specialty trainees and their ability to coordinate and collaborate for research.CURB-65, NEWS2 and qSOFA underestimate 30-day mortality among patients admitted to the hospital with COVID-19. CURB-65 and NEWS2 were slightly better at predicting early mortality. However, our data suggest CURB-65 should not be used to prognosticate in the setting of COVID-19 pneumonia since low CURB-65 scores were associated with high mortality rates. We provide a set of clinical parameters which appear relevant to outcomes in COVID-19 and should be considered in future studies aimed at deriving COVID-19-specific prognostic tools.