M age = 14.32, SD = 1.67) who had a dating relationship at the time or in the past 12 months, participated in this study. The results showed a higher prevalence for cyber-control than cyber-aggression victimization, and positive correlations of CDV victimization with depressive mood and cyberbullying victimization in boys and girls. Positive correlations with loneliness were also observed for girls. The average effect size of the aforementioned correlations was large for girls and medium for boys. Both boys and girls who were frequent victims of CDV also suffered more cyberbullying by peers than those who were never, and occasionally, cyber victimized by their partners. Girls who were frequent victims of CDV also reported higher scores for loneliness and depressive mood, with a small average effect size. All these results highlight close relations between cyberbullying and CDV in adolescents, being necessary to pay greater attention to possible experiences of poly-victimization, and a worse psychosocial adjustment in frequently victimized girls than boys. These findings may be useful for developing more effective intervention programs.Currently, cyber dating violence (CDV) is a serious health problem among adolescents due to their frequent use of communication technologies in their romantic relationships including the use of these technologies to perpetrate dating violence. However, research on this topic is recent and more studies about victims’ psychosocial adjustment are needed. The objectives of this study were to analyze the prevalence of CDV victimization according to frequency  and type (cyber control and cyber-aggression) and to explore their relations with loneliness, depressive mood and cyberbullying victimization. A total of 604 adolescents ( Cyber dating violence (CDV) is an increasing public health problem because adolescents constantly use information and communication technologies (ICTs) in their daily lives, including their interpersonal relationships ,2,3. CurPrevious studies have analyzed CDV prevalence among adolescents, and have shown worrying percentages of adolescents involved in this cyber violence ,25,26. NIn addition, relations between CDV victimization and psychosocial adjustment might be different in adolescent boys and girls. Although some previous studies have not found any gender differences in CDV victimization prevalence ,33, otheCDV victimization has a very negative impact on adolescents’ psychosocial adjustment. This cyber violence can occur constantly, and the humiliating and threatening messages by partners can take place 24/7, without victims being able to stop attacks. Additionally, a victim’s humiliating photos and information can quickly be spread to a wide audience. All these characteristics increase victims’ feelings of helplessness and hopelessness, who then feel unable to avoid the cyber aggression ,37,38,39Another important indicator of psychosocial adjustment that could be related to suffering CDV is loneliness. Feelings of loneliness have been related to offline dating violence victimization , and socThe current use of ICTs by people in their daily lives also increases cyberbullying in adolescents and young adults . CyberbuLinks between cyberbullying and CDV have been previously reported ,21, and Taking into account previous research and the need for more in-depth analysis of the relations of CDV victimization with cyberbullying victimization, loneliness and depressive mood in adolescents, three objectives were proposed in this study. The first objective was to analyze the prevalence of CDV victimization in adolescent boys and girls by taking into account the frequency  and type (cyber-control and cyber-aggression) of CDV suffered by adolescents. The second objective was to analyze the correlations between CDV victimization (cyber-control and cyber-aggression), feelings of loneliness, depressive mood and cyberbullying victimization (direct and indirect). Finally, the third objective was to analyze any possible differences in loneliness, depressive mood and cyberbullying victimization in adolescents with a different type (cyber-control and cyber-aggression) and frequency  of CDV victimization. Regarding these objectives, we proposed three hypotheses that were justified in the empirical results reported in the previous literature.Hypothesis 1.The prevalence of cyber-control victimization in adolescent couples will be higher than cyber-aggression victimization for both boys and girls. More specifically, we hypothesize a prevalence higher than 30% for cyber-control victimization and higher than 10% for cyber-aggression victimization. Borrajo et al.  observedHypothesis 2.CDV victimization (cyber-control and cyber-aggression) will be positively correlated with loneliness, depressive mood and cyberbullying victimization (direct and indirect) in both boys and girls. In a previous study carried out by Borrajo and Gámez-Guadix  with a sHypothesis 3.2 = 0.031, depressive mood: η2 = 0.045). Moreover, close relations between offline peer victimization and offline dating violence victimization  have been observed [Adolescent boys and girls who frequently suffer CDV victimization (cyber-control or cyber-aggression) will report significantly higher scores for loneliness, depressive mood and cyberbullying victimization (direct and indirect) than adolescent boys and girls who have never suffered CDV victimization. Possible differences in loneliness, depressive mood and cyberbullying victimization according to the frequency and type of CDV victimization suffered by adolescents have not been previously analyzed. However, in a previous study with 672 adolescents aged 12–17 years , those wobserved , with meM age = 14.11; SD = 1.75). Regarding gender, 49.4% of these adolescents were boys  and 50.6% were girls . They all studied in three public compulsory secondary education schools in the Valencian region (east Spain). Most adolescents (70.2%) lived with both parents, 18.8% lived with their mothers, 2.5% lived with their fathers, 6.1% lived in shared custody situations, and 2.4% with other relatives. Of this initial sample, only the adolescents in a romantic relationship at the time, or in the past 12 months, were included in this study. These adolescents were asked to fill in scales about their romantic partner, by referring to the latest relationship they were in or had been in. They were asked to think about their last romantic relationship that lasted longer than a single date/a single encounter.Our initial research sample comprised 1063 adolescent boys and girls, aged between 12 and 17 years  and girls  was similar. The highest percentages of adolescents were 13 (24.8%), 14 (19%), and 15 (18%) years old, with lower percentages for the 12- (13.4%), 16- (11.6%) and 17-year-olds (13.1%). In this final sample, 67.8% of adolescents lived with both parents, 21.9% only with their mothers, 2% only with their fathers, 5.3% in shared custody situations and 2% with other relatives. Most adolescents indicated having a heterosexual romantic relationship (95.5%), and only 4.5% admitted having a homosexual romantic relationship. Regarding the length of their romantic relationship, the majority of adolescents (52.9%) reported romantic relationships lasting between 1 and 6 months, with lower percentages of romantic relationships lasting less than 1 month (15.8%), between 6 months and 1 year (17.5%) and over 1 year (13.4%).By considering the aforementioned inclusion criterion, the final study sample included 604 adolescents, 262 boys (43.4%) and 342 girls (56.6%), aged between 12 and 17 years. The mean age of boys . Trained researchers administered the instruments to the adolescents on one school day, and informed them that their participation in the study was voluntary and anonymous, their data were confidential and they could drop out of the study at any time. None refused to participate in this research. This study was approved by The Ethics Committee of the University of Valencia (Protocol Number: H1456762885511).M = 1.29, SD = 0.52) were assigned to the group of “frequent cyber-control victimization”. Those adolescents who reported having never been victims of any behavior of cyber-control in their dating relationships were assigned to the group “never cyber-control victimization”. Finally, those adolescents who had suffered some cyber-control victimization behaviors, but whose scores did not exceed the mean score by one standard deviation, were assigned to the group “occasional cyber-control victimization”. Likewise, the adolescents whose scores exceeded the mean cyber-aggression victimization score by one standard deviation  were assigned to the group of “frequent cyber-aggression victimization”. The adolescents who reported having never been victims of any cyber-aggression behavior were assigned to the group “never cyber-aggression” and those who had suffered some cyber-aggression victimization behaviors, but their scores did not exceed the mean score by one standard deviation, were assigned to the group “occasional cyber-aggression”. We analyzed the prevalence of these different types and frequencies of CDV victimization separately for boys and girls.First, CDV victimization (cyber-control and cyber-aggression) prevalence in adolescent boys and girls was calculated. In the prevalence analysis, we considered not only the type (cyber-control and cyber-aggression), but also the frequency , of CDV victimization suffered by adolescents. Following the criteria used in other previous studies ,61, we cr. Cohen’s d and eta-square values were used to interpret the effect sizes of mean differences estimated with the Student’s t test and MANOVA, respectively.Next, Pearson correlations among CDV victimization (cyber-control and cyber-aggression), loneliness , depressive mood and cyberbullying victimization (direct and indirect) were calculated for boys and girls. Possible gender differences in all these variables were analyzed by the Student’s t test for independent samples. The possible differences in loneliness , depressive mood and cyberbullying victimization (direct and indirect) between the adolescents suffering a different type and frequency of CDV victimization were analyzed by applying a multivariate analysis of variance (MANOVA). A first multivariate analysis of variance was performed to compare possible differences in loneliness, depressed mood and cyberbullying victimization according to the frequency of cyber-control suffered by adolescents . A second multivariate analysis compared possible differences in the same outcome variables according to the frequency of cyber-aggression suffered . These analyses were carried out separately for boys and girls and were all performed with the SPSS-26 statistical package. To interpret the effect sizes of the correlations among variables, we followed the guidelines proposed by Funder and Ozer  regardin2(2) = 5.530; p > 0.05). Cyber-aggression prevalence was significantly lower than cyber-control victimization , but was also worrying. The results indicated that 11.6% of all adolescents had suffered at least one cyber-aggression behavior in their dating relationships. This cyber-aggression victimization was occasional for 4.1% of adolescents and frequent for 7.5% of them. The analysis of gender differences in adolescents’ distribution across these frequency groups showed significant differences between boys and girls (χ2(2) = 10.970; p < 0.01). A higher frequent cyber-aggression victimization prevalence was found for boys than for girls.Regarding CDV victimization prevalence , almost The results of analyzing differences in loneliness , depressive mood and cyberbullying victimization (direct and indirect) in adolescent boys and girls with distinct cyber-control victimization experiences  are shown in The results about cyber-aggression victimization also showed significant differences in more variables in girls than boys see . In boysA first objective of this study was to analyze CDV victimization prevalence in adolescent boys and girls by considering type and frequency of cybervictimization. The results of the present study confirmed a higher cyber-control victimization prevalence ,21,25,28Moreover, our results not only showed that cyber-control victimization prevalence was higher than cyber-aggression victimization, but most of the adolescents who had suffered this type of CDV reported occasional cyber-victimization (30.5%). Almost one in three adolescents reported suffering occasional cyber-control by their partner, while 13.6% reported situations of frequent cyber-control. These results confirm the initial hypothesis by showing a higher prevalence for occasional cyber-control victimization in adolescent couples, and could also indicate a certain normalization of such behaviors in these couples. Regarding cyber-aggression, the percentage of occasional victimization was similar and even lower (4.1%) than the percentage of frequent victimization (7.5%). In cyber-aggression, adolescent boys reported more frequent victimization than girls. Borrajo and Gámez-Guadix  also obsRegarding the correlations among CDV victimization (cyber-control and cyber-aggression) and adolescents’ psychosocial adjustment, the results showed some differences between adolescent boys and girls. Although positive correlations between depressive mood and CDV (cyber-control and cyber-aggression) victimization were confirmed in both boys and girls ,28, emotThe analyses carried out to compare adolescents’ groups with different CDV victimization type and frequency gave some interesting results. In cyber-control victimization, significant differences appeared between frequently and never victimized adolescents (boys and girls) in depressive mood and indirect cyberbullying victimization, but significant differences were not found in these variables between never and occasionally victimized boys and girls. The effect sizes of the mean differences were from small to medium (with effect sizes ranging from 0.029 to 0.096). However, even small effect sizes can be relevant. As it has been pointed out in the literature , the effAnother interesting finding was the gender differences observed in the relations between cyber-control victimization and loneliness. Adolescent boys suffering frequent, occasional or never cyber-controlled by their partners reported similar feelings of loneliness and similar assessment of their social network. In contrast, girls frequently victimized reported more feelings of loneliness and assessed their social network worse than those never victimized. Loneliness is defined as a negative emotional response to a discrepancy between the desired and achieved quality of one’s social network . In adolRegarding cyber-aggression victimization, not only was its prevalence lower than cyber-control, but also fewer differences were observed between adolescents frequently and occasionally cyber victimized. These two groups  reported similar direct cyberbullying victimization levels, which suggests that direct cyberbullying might be related more to cyber-aggression than cyber-control. Both cyber-aggression by partners and direct cyberbullying by peers are direct attacks on victims in order to harm them, and the victims of these two forms of cyber violence could share common characteristics, such as a risky use of electronic devices. Walrave et al.  highlighThis study has some limitations that must be considered. First, it is a cross-sectional study and it is, therefore, impossible to provide explanations about the causality and influence of one variable on another. Longitudinal studies are necessary to explore the causal relationships between these variables. Another limitation of this study is that it did not consider the severity of the suffered CDV behaviors. Although a distinction between cyber-control and cyber-aggression behaviors was made in this study, the severity of suffered cyber-aggressions  was not taken into account. The severity of cyber aggressions suffered by adolescent boys and girls could differ. Moreover, the possible co-occurrence of offline and online dating violence victimization was not contemplated. Both the severity of cyber-aggressions and the co-occurrence of online/offline dating violence victimization could imply different consequences for adolescents’ psychosocial adjustment, and they should be considered in future studies. Another limitation of this study was the use of self-report measures, which may include some biases based on adolescents’ perceptions. These measure types are frequent in studies on victimization and aggressive behavior in adolescents. Nevertheless, it would be worth jointly including other sources of information, such as partners. The possible bi-directionality of CDV also needs to be considered. As mutual verbal-emotional aggressions are frequent in adolescent couples , it woulThe present study provides novel and interesting findings about cyber-control and cyber-aggression victimization prevalence in adolescent couples and how it relates to adolescents’ psychosocial adjustment and cyberbullying victimization. Regarding prevalence analyses, not only the type of CDV victimization (cyber-control and cyber-aggression), but also the frequency of CDV victimization suffered and the possible gender differences have been analyzed. Results showed a higher prevalence of cyber-control victimization than cyber-aggression victimization, mainly for experiences of occasional cyber-control victimization with a similar prevalence in boys and girls. The high prevalence of cyber-control behaviors  reported suffering at least one cyber-control behavior by their partners) suggests that some of these behaviors would not be perceived as cyber abuse by adolescents. Although the cyber-aggression victimization prevalence was lower (11.6%), these data highlight the need to develop prevention programs to prevent CDV among adolescents.The results of this study also showed strong correlations between being a victim of cyberbullying and suffering CDV, which suggests the existence of possible common risk factors and the need to pay more attention to adolescents suffering poly-victimization situations. Studies on the relationships between cyberbullying and CDV victimization are still very scarce, and this study highlights close links between these two forms of cybervictimization among adolescents. Furthermore, it would be worth developing intervention programs aimed at jointly preventing cyberbullying and CDV. These intervention programs should help adolescents to be aware of the risky uses of their social networks, to know how to identify abusive behaviors (in relationships with both their peers and their partners) and to teach them to adequately cope with situations of cyber violence.Regarding the psychosocial adjustment in those adolescents suffering CDV, the obtained results suggest a greater vulnerability of adolescents frequently victimized compared to those occasionally victimized, and the need to continue analyzing gender differences. In addition, the findings about the relations among CDV victimization, depressive mood and loneliness in adolescents showed interesting differences between boys and girls. Adolescent boys and girls suffering frequent cyber-control reported more depressive mood than those never victimized, but frequently victimized girls also indicated more emotional loneliness and assessed their social network worse. In cyber-aggression victimization, the differences between boys and girls were bigger. Frequently cyber-victimized adolescent girls, but not boys, reported more depressive mood, more emotional loneliness and assessed their social network worse. All these results indicate a worse psychosocial adjustment in adolescent girls suffering cyber-control and cyber-aggression by their partners. Future research should continue studying these gender differences in CDV for developing more effective intervention programs.


Evidence is conflicting about how human immunodeficiency virus (HIV) modulates coronavirus disease 2019 (COVID-19). We compared the presentation characteristics and outcomes of adults with and without HIV who were hospitalized with COVID-19 at 207 centers across the United Kingdom and whose data were prospectively captured by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) World Health Organization (WHO) Clinical Characterization Protocol (CCP) study.We used Kaplan-Meier methods and Cox regression to describe the association between HIV status and day-28 mortality, after separate adjustment for sex, ethnicity, age, hospital acquisition of COVID-19 , presentation date, 10 individual comorbidities, and disease severity at presentation (as defined by hypoxia or oxygen therapy).P < .001) and had fewer comorbidities, more systemic symptoms and higher lymphocyte counts and C-reactive protein levels. The cumulative day-28 mortality was similar in the HIV-positive versus HIV-negative groups , but in those under 60 years of age HIV-positive status was associated with increased mortality . Mortality was higher among people with HIV after adjusting for age , and the association persisted after adjusting for the other variables  and when restricting the analysis to people aged <60 years .Among 47 592 patients, 122 (0.26%) had confirmed HIV infection, and 112/122 (91.8%) had a record of antiretroviral therapy. At presentation, HIV-positive people were younger  hospitalized with coronavirus disease 2019 (COVID-19) had an age-adjusted 47% higher risk of day-28 mortality compared with a large population of HIV-negative people within the same data set. The effect persisted after adjusting for sex, ethnicity, and major comorbidities. Older age and presence of comorbidities including immunosuppression are recognized to increase the severity of coronavirus disease 2019 (COVID-19) . HoweverSeveral case series and observational cohort studies have described the outcomes of COVID-19 in PWH across Europe , Asia 1, 19, andTo characterize the presenting characteristics and outcomes of COVID-19 related hospitalization in PWH relative to those without HIV in the United Kingdom (UK), we analyzed data collected within the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) World Health Organization (WHO) Clinical Characterization Protocol (CCP), the largest prospective observational study of patients admitted to hospital with COVID-19 worldwide .The ISARIC WHO CCP-UK is an ongoing prospective cohort study in hospitals in England, Scotland, and Wales . The stuPneumocystis jirovecii prophylaxis in the absence of non-HIV indications (n = 2), or directly with a site investigator. Individuals with missing HIV status and those with unconfirmed HIV-positive status were excluded.Baseline was defined as the date of hospital admission or symptom onset . We included individuals with a baseline date that was on or before 4 June 2020 for whom ≥14 days had elapsed at data extraction on 18 June. Individuals with missing admission date were excluded. Where the date of symptom onset was missing, we assumed that symptoms began on the date of the first SARS-CoV-2 PCR test. Based on the date of symptom onset relative to the date of admission, the infection was classed as community-acquired (symptom onset <3 days), indeterminate (3–7 days), probable hospital-acquired (8–14 days), and definite hospital-acquired (>14 days). Using the CRF version 9.2 , demogra2 or Fisher exact test . For all individuals, follow-up ended on the date of death. Patients discharged for home palliative care were considered to have died 3 days afterward. Follow-up was right-censored at day 28 for those remaining alive as an inpatient or for those who were discharged  prior to day 28. No deaths were recorded among PWH after day 28. Follow-up was censored for patients transferred to another facility at date of transfer; among those with unknown outcome, it was censored on the last recorded date of follow-up where they were known to be alive. For patients who died, were transferred, or discharged on the date of admission or who had no further follow-up recorded beyond the first day, we recorded 0.5 days of follow-up. The primary analysis used a Kaplan-Meier approach to display the cumulative mortality over this period and in strata defined by sex and age. Cox proportional hazards regression with the Efron method for ties was then used to describe the association of mortality with HIV status, before and after adjustment for the following potential confounders: sex, ethnicity, age (in quadratic form), indeterminate/probable hospital acquisition of COVID-19 (as defined above), and 10 separate comorbidities at admission . These variables were selected a priori. We also included adjustment for the baseline date to account for changes in mortality over time. For partially missing comorbidity data, we assumed missing comorbidities were absent. Participants with completely missing comorbidity data were excluded from these adjusted analyses. We fitted a further model adjusting for disease severity at presentation, defined as oxygen saturation <94% on air or receiving oxygen therapy, to assess whether risk of mortality in PWH could be explained by a different stage of disease advancement at hospitalization. Finally, we repeated the same analysis among individuals aged ≤70 years. A series of sensitivity analyses were performed: (i) we repeated the analyses after censoring follow-up on the day of discharge; (ii) we included those with definite hospital-acquired COVID-19; (iii) we used symptom onset date as the baseline date for all; (iv) we excluded PWH lacking a record of ART; (v) we excluded those without a recorded positive SARS-CoV-2 PCR result; (vi) we calculated propensity scores for HIV-positive status using a logistic regression model based on sex, ethnicity, age (in quadratic form), indeterminate/probable hospital acquisition of COVID-19, smoking status, baseline date, and 10 comorbidities, and included the propensity score in a univariate Cox regression model for death at 28 days; (vii) we considered a binary endpoint of 14-day mortality and performed logistic regression (with the same confounder adjustment as described above); and (viii) we used a competing risks regression model with discharge as a competing risk for mortality. In PWH, we used a Cox proportional hazard model to investigate associations with day-28 mortality. Analyses were conducted in Stata v16.1 .Presenting characteristics were compared between HIV-positive and HIV-negative people and between PWH who died and those who survived at 28 days using Wilcoxon rank sum tests (for continuous variables) and Pearson χ Approval was granted by the following Ethics Committees: South Central-Oxford Ref /SC/0149,ISARIC CCP-UK recorded 53 993 people with COVID-19 between 17 January and 18 June 2020. After excluding non-eligible participants , we inclP < .001) (P = .002) . PWH were more likely to present with fever, headache, myalgia, and tachycardia, and to have cough and chest pain. Respiratory rate, occurrence of tachypnoea and hypoxia, and radiological evidence of chest infiltrates did not differ significantly between the 2 groups. PWH presented with lower total white blood cell and platelet count but higher lymphocyte count and C-reactive protein (CRP)   and comp = .002) . PWH werin (CRP) .P = .35) (P = .16 P < .001).After adjustment for sex, ethnicity, age, baseline date, indeterminate/probable hospital acquisition of COVID-19, and 10 comorbidities, the odds of admission to critical care were similar regardless of HIV status  . By day P = .35) , 30 . Results did not change after adjusting for sex or ethnicity. In contrast, adjustment for age resulted in a change in the direction of the association . Results were similar after adjustment for sex, ethnicity, age, baseline date, indeterminate/probable hospital acquisition of COVID-19 and 10 comorbidities, and following additional adjustment for disease severity at presentation. When restricted to people <60 years, the analysis yielded an adjusted HR of 2.87 . Sensitivity analyses showed consistent results . The latter adjustment considered that doctors may be more likely to admit HIV-positive adults with COVID-19 despite less severe symptoms.The influence of age, sex, and ethnicity on COVID-19 outcomes is currently debated , 25. PWHAlthough there is a recognized interplay between HIV and comorbidities, neither omitting the adjustment for comorbidities nor adjusting for separate comorbidities modified the association. PWH had fewer comorbidities, notably lower prevalence of chronic pulmonary disease and malignancies, and this is largely a function of their younger age. HIV-positive people who died were older and were more likely to suffer from obesity and diabetes with complications than those who survived to discharge. Similar trends have been seen in the general population , 25. AltEvidence about the interplay between HIV and COVID-19 is not entirely consistent . A case-A key strength of this study was the ability to perform a direct comparison of people with and without HIV in the same data set, and to account for age, sex, ethnicity, and key comorbidities.The data for this study were collected during the first peak of the UK COVID-19 epidemic, and there are missing data, including 2742 patients with missing HIV status, who were excluded from the analysis. We also excluded 10 people initially recorded as having HIV but whose HIV status could not be confirmed; this group was similar to the HIV-negative group, with a median age of 81, suggesting that their initial HIV record was incorrect. Thus, these missing data are unlikely to affect the results.Pneumocystis jirovecii prophylaxis recorded in their admission medications, suggesting that the likelihood of PWH in our study being severely immunosuppressed was overall low.Our focus was on the effect of HIV-positive status on day-28 mortality among people hospitalized with COVID-19. We did not address risk factors for a COVID-19 diagnosis or hospitalization among PWH, or the suggested modulating role of certain antiretroviral agents . We also3, a threshold indicative of significant immunosuppression [3 [Despite effective ART and normalized CD4 cell counts, a subset of PWH continue to experience immune activation, inflammation, and a procoagulatory state , which mpression , 29. Furssion [3 , 29. Thussion [3 . ImmunolIn conclusion, our data are limited by the relatively small number of people with HIV included in the study, and the findings should be interpreted with caution. Nonetheless, after careful considerations, our analysis of the outcomes of patients hospitalized with COVID-19 in the United Kingdom shows an increased risk of day-28 mortality due to HIV-positive status. As the pandemic continues to spread, including in areas of increased HIV prevalence, it is important to record the HIV status of people hospitalized with COVID-19 and gather further data to corroborate our findings and confirm the population-specific determinants of outcomes. Meanwhile, emphasis for PWH should be placed on early HIV diagnosis, prompt ART initiation, and optimized screening for and control of comorbidities, including obesity and diabetes.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciaa1605_suppl_Supplementary_Materials_1Click here for additional data file.


The METastasis Reporting and Data System for Prostate Cancer (MET-RADS-P) guidelines are designed to enable reproducible assessment in detecting and quantifying metastatic disease response using whole-body magnetic resonance imaging (WB-MRI) in patients with advanced prostate cancer (APC).The purpose of our study was to evaluate the inter-observer agreement of WB-MRI examination reports produced by readers of different expertise when using the MET-RADS-P guidelines.Fifty consecutive paired WB-MRI examinations, performed from December 2016 to February 2018 on 31 patients, were retrospectively examined to compare reports by a Senior Radiologist (9 years of experience in WB-MRI) and Resident Radiologist (after a 6-months training) using MET-RADS-P guidelines, for detection and for primary/dominant and secondary response assessment categories (RAC) scores assigned to metastatic disease in 14 body regions. Inter-observer agreement regarding RAC score was evaluated for each region by using weighted-Cohen’s Kappa statistics (K).The number of metastatic regions reported by the Senior Radiologist (249) and Resident Radiologist (251) was comparable. For the primary/dominant RAC pattern, the agreement between readers was excellent for the metastatic findings in cervical, dorsal, and lumbosacral spine, pelvis, limbs, lungs and other sites (K:0.81–1.0), substantial for thorax, retroperitoneal nodes, other nodes and liver (K:0.61–0.80), moderate for pelvic nodes (K:0.56), fair for primary soft tissue and not assessable for skull due to the absence of findings. For the secondary RAC pattern, agreement between readers was excellent for the metastatic findings in cervical spine (K:0.93) and retroperitoneal nodes (K:0.89), substantial for those in dorsal spine, pelvis, thorax, limbs and pelvic nodes (K:0.61–0.80), and moderate for lumbosacral spine (K:0.44).We found inter-observer agreement between two readers of different expertise levels to be excellent in bone, but mixed in other body regions. Considering the importance of bone metastases in patients with APC, our results favor the use of MET-RADS-P in response to the growing clinical need for monitoring of metastasis in these patients. Advanced Prostate Cancer (APC) typically demonstrates a good initial response to androgen deprivation therapy (ADT), but in the course of 1 to 3 years, almost inevitably progresses into metastatic Castration Resistant Prostate Cancer (mCRPC)  and lossThe early identification of treatment failure in men with mCRPC on systemic therapy could spare them unnecessary treatment and potential toxicity while reducing the costs of ineffective treatments and decreasing the time to initiation of a potentially effective, next-line treatment . With upNext generation imaging techniques have better accuracy for detecting metastases than computed tomography (CT) and bone scintigraphy (BS) . MoreoveThe recently published “METastasis Reporting and Data System for Prostate Cancer” (MET-RADS-P) guidelines  provide We analyzed therapy response in 50 pairs of WB-MRI examinations performed on 31 APC patients with hormone sensitive and castration resistant disease who had underwent at least two WB-MRI examinations in our institution between December 2016 and February 2018 for the follow-up of anti-cancer therapy. Sixteen of the patients had one prior WB-MRI examination , 11 patients had two prior examinations , and four patients had three prior examinations . Inclusion criteria were the presence of metastatic cancer in previous WB-MRI and ongoing follow-up with WB-MRI performed in our institution. The median age of the included patients was 68 years . The local ethical committee approved this retrospective study, and waived the requirement for specific consent from the patients.fit, Siemens Healthineers, Erlangen, Germany) equipped with works-in-progress software for slice-specific shimming . The WB-MRI acquisition protocol and post-processing of images . Where patients had more than one examination pair in the study, the radiologists were not blinded to their results regarding prior examination pairs. According to MET-RADS-P guidelines, the presence or absence of metastasis was reported for each of 14 body regions: primary disease, 7 skeletal regions, 3 nodal and 2 visceral sites and other sites [p-value of < 0.05 was considered to be statistically significant.MET-RADS-P based findings were summarized by site and the inter-observer agreement between the Senior Radiologist and Resident Radiologist for region-based disease detection, assignment of RAC scores to metastases, and patient management was evaluated for each region by weighted-Cohen’s Kappa statistics (K). Inter-observer agreement was interpreted as none to slight (K:0.01–0.20), fair (K:0.21–0.40), moderate (K:0.41–0.60), substantial (K:0.61–0.80) or excellent (K:0.81–1.00). Statistical analysis was carried out with SAS software, version 9.4. A n = 8 patients), followed by GS 4 + 3  and GS 4 + 5 . The remaining 12 patients had been treated with radiotherapy. Further details of therapies in use at the time of the WB-MRI examination(s) are given in Table The majority of patients had undergone radical prostatectomy (19 of 31 patients). Amongst these patients, a Gleason Score (GS) of 4 + 4 was the most common diagnosis  and 23 in mCRPC at the time of examination. The distribution of metastases for each patient at the outset of the study is reported in Table The number and distribution of metastatic sites reported was comparable between readers Table , with thThe RAC patterns findings for each region are summarized in Supplementary Table EThe agreement between readers for primary/dominant RAC pattern Table  was exceThe agreement between readers for secondary RAC pattern Table  was exceThe primary disease was evaluated only in the 12 patients who had not undergone prostatectomy. The inter-observer agreement in the primary/dominant RAC pattern at the site of primary disease was fair (weighted kappa = 0.21 (0.00–0.50)). Inter-observer agreement for the secondary RAC patterns at the site of primary disease was not evaluated due to the lack of findings in our cohort.On a per-patient basis Fig. , the radOur cohort of 31 patients was relatively balanced between radical prostatectomy and radiotherapy as active treatment of primary tumor (19 vs. 12), and the number of WB-MRI evaluations was balanced between hormone sensitive and castration resistant states (27 vs. 23). Our observations therefore, are unlikely to be biased by treatment modality or clinical state. A majority of our cohort showed bone metastases. This is not surprising as the presence of metastasis was an inclusion criterion of this study, and bone is the most common site of metastasis from prostate cancer.Overall, the Resident and Senior Radiologists detected a similar number of metastatic sites . Both detected bone metastases in 47 WB-MRI evaluations, and they were in full agreement for metastases to liver, lung and pleura, and other sites (9 metastases). They agreed well on the number of metastatic nodes (26 by the Resident Radiologist vs. 25 by the Senior Radiologist). Our results suggest, therefore, that the ability to detect of metastases with WB-MRI may not be heavily influenced by reader expertise. This is consistent with the excellent diagnostic performance reported for the detection of metastases with WB-MRI  where hiIn our cohort, we found high inter-observer agreement in primary/dominant RAC assessment  for all regions except the pelvic nodes. Our inter-observer agreement for response to therapy was higher for bone metastases than for the other body regions. Three considerations likely contribute to this finding. First, our population was composed exclusively of APC patients, for whom the dominant sites of metastases are bone and lymph nodes. Consequently, just four patients had metastases to other soft tissues  in a region, and thus is dependent on the reader’s ability to identify the differences in response present in a small subgroup of metastases Fig. . AssessiNotably, agreement in the assessment of response at the site of primary tumor was only fair. This assessment is however, dependent on just the 12 patients who had not undergone prostatectomy. This result could be related to the known difficulties in the evaluation of post-treatment imaging of prostate cancer, likely related to the less experience reader suffered more in this context than the experienced.While MET-RADS-P aims to provide a more complete view of the heterogeneity of response throughout the extent of metastatic disease, as opposed to a single global summary value, ultimately it serves to support decision-making regarding the maintenance or change of therapy. On a per-patient basis Fig.  we foundAn important limitation of the present study is that it involved just two readers is a single institution, with the less experienced Resident Radiologist having been trained by the Senior Radiologist as opposed to the readings being performed by two certified radiologists of different levels of experience in WB-MRI. The Resident Radiologist received training “in-house” in a high volume service, but there is no published data regarding the reader learning curve and requisites for competent reporting in WB-MRI. The large difference in experience likely contributed to the modest inter-observer agreement we observed; particularly for the assessment of secondary RAC where reader training and experience would be expected to play a significant role. The generally good agreement between experienced and inexperienced readers suggests that MET-RADS-P does in fact promote consistent interpretation across readers, but may also be an artifact of the training environment. The fact that the radiologists were not blinded to clinical data or the results of prior examination pairs may have led to bias in their reporting. We believe however, that providing the information in this way reflects clinical practice better than would be achieved with isolated review of examination pairs. Further, as an inclusion criterion was the presence of metastases on a WB-MRI as detected by the Senior Radiologist during clinical routine, the results do not necessarily generalize to the wider population of patients undergoing WB-MRI for metastasis detection and treatment monitoring. Finally, we note that comparator examinations with conventional MRI or CT were not available. Thus, we were not able to verify whether the moderate to substantial agreement between radiologists in regards to lymph nodes is accompanied by inferior sensitivity in detecting lymph node metastases. This is an important consideration for APC patients where lymph node spread is common. Studies with a wider sampling of readers in a larger population of patients, and validation of performance are needed to validate our results.We found inter-observer agreement between readers who have different levels of expertise in WB-MRI to be excellent in bone, but mixed in other body regions. Considering the importance of bone metastases assessment in patients with APC, our results favor the use and application of MET-RADS-P in response to the growing clinical need for accurate monitoring of metastasis and improve management in these patients in the era of precision oncology.Additional file 1 : Table E1. WB-MRI scanning protocol.Additional file 2 : Table E2. Distribution of primary/dominant and secondary RAC scores by MET-RADS-P region* as reported by the Resident Radiologist (RR) and Senior Radiologist.


What is the geographic distribution across the US and prevalence of Medicaid-claimant obstetrician-gynecologists who are trained to prescribe buprenorphine?In this cross-sectional study including 31 211 Medicaid-claimant obstetrician-gynecologists, fewer than 2% were trained to prescribe buprenorphine. In addition, these physicians were more likely to work in primarily suburban counties.Results of this study suggest that an opportunity exists for obstetrician-gynecologists to contribute to expanding the workforce of clinicians who can prescribe buprenorphine to further address the opioid epidemic’s association with maternal and infant morbidity and mortality. The incidence of opioid use during pregnancy is increasing, and drug overdoses are a leading cause of postpartum mortality. Most women who are pregnant do not receive medications for treatment of opioid use disorder, despite the mortality benefit that these agents confer. Furthermore, buprenorphine is associated with milder symptoms of neonatal abstinence syndrome (NAS) compared with methadone.To describe the prevalence and geographic distribution across the US of obstetrician-gynecologists who can prescribe buprenorphine (henceforth described as X-waivered) in 2019.A cross-sectional, nationwide study linking physician-specific data to county- and state-level data was conducted from September 1, 2019, to March 31, 2020. Data were obtained on 31 211 obstetrician-gynecologists who accept Medicaid insurance through the Centers for Medicare & Medicaid Services Physician Compare data set and linked to the Drug Addiction Treatment Act buprenorphine-waived clinician list.State-level NAS incidence and county-level uninsured rates and rurality.Prevalence and geographic distribution of obstetrician-gynecologists who are trained to prescribe buprenorphine.P = .04) compared with those in counties with greater than 15% uninsured residents. Compared with those located in metropolitan counties, obstetrician-gynecologists in suburban counties  were more likely to be X-waivered . Compared with states with an NAS rate of 5 per 1000 births or less, obstetrician-gynecologists in states with an NAS rate of 15 per 1000 births or greater had nearly 5 times the odds of being X-waivered . Obstetrician-gynecologists without hospital privileges were more likely to be X-waivered .Among the 31 211 identified obstetrician-gynecologists, 18 710 (59.9%) were women. Most had hospital privileges (23 236 [74.4%]) and worked in metropolitan counties (28 613 [91.7%]). Only 560 of the identified obstetrician-gynecologists (1.8%) were X-waivered. Obstetrician-gynecologists in counties with fewer than 5% uninsured residents had nearly twice the odds of being X-waivered (adjusted odds ratio [aOR], 1.59; 95% CI, 1.04-2.44; Fewer than 2% of obstetrician-gynecologists who accept Medicaid are able to prescribe buprenorphine, and their geographic distribution appears to be skewed in favor of suburban counties. This finding suggests that there is an opportunity for health systems and professional societies to incentivize X-waiver trainings among obstetrician-gynecologists to increase patients’ access to buprenorphine, especially during pregnancy. This cross-sectional study examines the prevalence and geographic distribution within the US of obstetrician-gynecologists who are able to prescribe buprenorphine for women who are pregnant. Although the overall proportion of admissions for drug treatment episodes among women who are pregnant has remained stable at 4%, the proportion reporting prescription opioids as the primary substance used increased substantially, from 1% to 19%, between 1992 and 2012.4 Per the American College of Obstetrics and Gynecology’s guidelines, the opioid agonist medications methadone and buprenorphine are the recommended treatments for OUD in pregnancy.4 Studies have reported that buprenorphine is not inferior to methadone on outcome measures assessing NAS and maternal and neonatal safety when treatment is initiated in the second trimester.7 Moreover, evidence suggests that buprenorphine confers additional benefits for neonates affected by NAS, including milder symptoms and shorter hospital lengths of stay, compared with neonates with in utero exposure to methadone.5Standard of care for OUD in pregnancy includes pharmacotherapy.11 Despite its effectiveness, buprenorphine remains inaccessible for many women with OUD who are pregnant. A study of treatment episodes for prescription OUD during pregnancy showed that medication for OUD was administered only during a third of treatment episodes,1 and a more recent study of women enrolled in Medicaid who were pregnant noted that nearly half of pregnant patients with OUD receive no medication for OUD.12Buprenorphine is a cost-effective treatment for OUD in adults, prevents complications associated with nonfatal overdoses, reduces the risk of injection-related infections, and reduces mortality risk.14 A recent study showed that only 0.4% of obstetrician-gynecologists were X-waivered.15 To our knowledge, despite increasing rates of OUD among women who are pregnant, no study has focused on the geographic distribution of X-waivers among obstetricians and gynecologists. The objective of this study, therefore, was to describe the geographic distribution and characteristics associated with X-waiver status among a broad sample of US obstetrician-gynecologists in relation to the severity of the opioid epidemic.The low rate of pregnant women with OUD receiving evidence-based care is due, in part, to barriers physicians face in terms of the ability to prescribe the medication. The Drug Addiction Treatment Act requires 8 hours of training for physicians and 24 hours for nurse practitioners and physician assistants to receive approval via a waiver  by the Drug Enforcement Agency to prescribe buprenorphine.STROBE) reporting guideline for cross-sectional studies. Because this study used only publicly available data, it was considered exempt by the University of Pennsylvania institutional review board. The initial data sets had identifiers that allowed us to merge them appropriately but were deidentified for the purpose of the analysis.This cross-sectional analysis linking physician-specific data to county- and state-level data across the US was conducted from September 1, 2019, to March 31, 2020. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (16 and the September 2019 Center for Medicare & Medicaid Services (CMS) Physician Compare data set.17 SAMHSA provides a data set of all clinicians with an X-waiver permitting them to prescribe buprenorphine in the US states and territories. The CMS Physician Compare is a data set of all physicians who have filed at least 1 Medicaid claim in the previous 3 months. The CMS data identify the specialty of the physician.Data for this study were acquired from 4 different sources. Individual physician data were acquired from the August 2019 Drug Enforcement Agency Substance Abuse and Mental Health Services Agency (SAMHSA) X-waivered practitioners data set18 which combines socioeconomic, demographic, and health statistics from corresponding US federal agencies’ publicly available data, as well as state-level NAS rates reported by the national inpatient sample data.19 The US Department of Agriculture Economic and Research Service’s rural-urban continuum was used to characterize counties as metropolitan or rural.20County-level data were acquired by geocoding all physicians’ work addresses provided by the CMS Physician Compare data set in ArcGIS, version 10.0 (Esri) and merging the geocoded data with county socioeconomic data from the Robert Wood Johnson Foundation’s 2019 County Health Rankings and Roadmaps,We selected the CMS Physician Compare data set based on their listed primary specialty for obstetrics and gynecology and merged this data set with the SAMHSA data based on unique identifiers: first name, last name, and zip code were first used to identify matches between the 2 databases. Duplicates were eliminated by using National Provider Identifier Number as provided by the CMS Physician Compare data set.21 Area-level variables used included county median household income, percentage of Black residents, percentage of Hispanic residents, rurality, percentage of uninsured residents, and most recently reported state NAS rate.Clinician-level baseline variables included sex, number of years since medical school graduation, and whether they have hospital privileges. We chose to compare individual physicians based on available variables with the aim of controlling for factors that may explain why some physicians are not X-waivered. In addition, if an obstetrician-gynecologist does not have hospital privileges, they likely do not work in labor and delivery settings, which is an important point of contact where women who are pregnant are increasingly diagnosed with OUD, as documented by the Centers for Disease Control and Prevention.t tests, statistical significance was defined as P < .05. Our model did not account for the nonrandomness of missing data.Descriptive statistics were used to describe X-waivered obstetrician-gynecologists and non–X-waivered obstetrician-gynecologists. A multivariable binomial logistic regression was used to determine independent associations with the presence or absence of X-waivered status. Analysis was conducted with Stata, version 16 (StataCorp LLC). Using paired 2-tailed 22 and the Doximity 2018 obstetrician-gynecologists workforce study.23In the CMS Physician Compare data set, 31 211 physicians were identified as being obstetrician-gynecologists as of September 13, 2019, representing approximately three-quarters of US obstetrician-gynecologists, according to the American Association of Medical Colleges’ most recent census of number of active physicians per specialty (2017)P < .001). X-waivered obstetrician-gynecologists had fewer mean (SD) years since medical school graduation (23.5 [11.5] years) compared with their non–X-waivered counterparts (24.5 [12.0] years) (P < .001).Linking this data set with the SAMHSA data set of buprenorphine-approved physicians yielded a total of 560 obstetrician-gynecologists (1.8%) who were X-waivered. P < .001) and not having hospital privileges  (P < .001). Obstetrician-gynecologists in counties with less than 5% uninsured residents had nearly twice the odds as those in counties with greater than 15% uninsured residents to be X-waivered .In the multivariate logistic regression (model 1), X-waivered status was associated with male sex  . The sta = .007) . For exaP = .002). Obstetrician-gynecologists without hospital privileges were more likely to be X-waivered . We performed a second multivariable regression with states’ fixed effects (excluding NAS rates and percentage of uninsured rates owing to collinearity) to account for differences in state-level policies and the landscape of the opioid epidemic. In this model, male obstetrician-gynecologists were also more likely to be X-waivered , as were those without hospital privileges .Compared with those located in large metropolitan areas (counties in metropolitan areas of ≥1 million people), obstetrician-gynecologists in suburban counties  were more likely to be X-waivered  with each increase in SD of number of years since medical school graduation  are less likely to receive any pharmacotherapy for OUD. When receiving pharmacotherapy, Black and Hispanic women are more likely to receive methadone than buprenorphine,41 These benefits are particularly important in the postpartum period, a challenging time in a woman’s life with drug overdoses being a leading cause of death.42 Use of buprenorphine extended-release, however, requires that patients have a history of receiving the immediate-release formulation. Evidence suggests that women with OUD who are pregnant in states most affected by the opioid epidemic face substantial barriers accessing both buprenorphine and methadone. Methadone practitioners are more likely than X-waivered clinicians to accept women who are pregnant, but rates of accepting pregnant women in both groups are low. In addition, Medicaid is accepted at low rates overall, and X-waivered clinicians accept cash payments at higher rates.44Concerns of retention in treatment, especially in the postpartum phase, may be addressed by initiation of the buprenorphine extended-release formulation. In the general population, patients receiving buprenorphine extended-release report higher treatment satisfaction, and the medication leads to greater positive, patient-centered outcomes.45The observed sex difference in the rates of X-waivered obstetrician-gynecologists in our study may be reflective of prior evidence that showed differences in practice styles, whereby male obstetrician-gynecologists were more likely to manage the nonreproductive health conditions of their patients, while female obstetrician-gynecologists were more likely to refer the patients to primary care physicians or other specialists.46 This lack of integration presents an opportunity for improving continuity and transitions in care, especially after key events such as the transition from birthing to outpatient postpartum care.The finding that obstetrician-gynecologists with hospital privileges are less likely to be X-waivered is in line with a recent study showing that, overall, X-waivered physicians are most likely to have primarily outpatient practices and not be integrated with hospital systems.25 Even among women with OUD who are pregnant and enrolled in Medicaid, primary care physicians and psychiatrists are the leading prescribers of buprenorphine, followed by obstetrician-gynecologists.47 Clinicians face barriers to becoming X-waivered, including low psychosocial support, time constraints, and stigma from colleagues and office staff, which altogether may also contribute to this low rate.50 Some obstetrician-gynecologists who are not X-waivered may work in collaboration with psychiatrists or primary care physicians to whom they refer their patients for buprenorphine, but studies show that women who are pregnant are unevenly screened and referred to treatment by their obstetrician-gynecologists after screening positive for substance use disorders,51 despite what guidelines recommend. Initiation of treatment after positive screening and bridging to long-term care is a useful practice to retain patients in treatment and is an increasing practice in emergency department settings.54 Screening can take place during prenatal care, as recommended by the American College of Obstetrics and Gynecology,4 or at delivery, in addition to newborn NAS screening. Not being X-waivered limits physicians’ ability to initiate and bridge patients to long-term treatments in case of a positive screening and patient interest in initiation of medications. These barriers, furthermore, contribute to racial/ethnic and socioeconomic disparities in access to buprenorphine.55The overall low number of obstetrician-gynecologists who are X-waivered may be associated with several factors, including existing barriers, stigma, and historical precedent. Historically, X-waivered physicians are more likely to be psychiatrists and primary care physicians. However, other specialties have seen significant increases in X-waiver status, including emergency medicine.56 but may not necessarily influence adoption of the X-waiver at the same rate.In terms of the association between NAS rates and the distribution of X-waivered obstetrician-gynecologists, our findings suggest the prevalence of X-waivered obstetrician-gynecologists tracks with NAS rates, although absolute numbers are low. Some states, however , show a relative lag, where NAS rates are relatively high, while the prevalence of X-waivered obstetrician-gynecologists is relatively low compared with other states. This relative lag may be due to local policies, such as states’ responses to the opioid epidemic. Regional socioeconomic factors contribute to NAS rates57 Given the increasing prevalence of OUD among women, and as substance use disorder moves toward greater integration with health services provision, X-waivered obstetrician-gynecologists could fill a gap in OUD care, family planning, and general gynecologic care for women with OUD. Our findings warrant further investigation into barriers that obstetrician-gynecologists face with regard to becoming X-waivered.Beyond pregnancy, there remains a role for X-waivered obstetrician-gynecologists. A study evaluating the reproductive needs of clients with substance use disorder noted that 83% of women and 58% of men would use family planning services if available at their place of treatment. In addition, only 53% of sexually active women reported using any form of contraception, and 20% reported using a highly reliable form of contraception.58 and over 80% of newborns with NAS are insured by Medicaid.59 A recent study reported that X-waivered physicians prescribe buprenorphine at varying rates, including some who do not prescribe buprenorphine.60 Our findings may thus not reflect the degree to which X-waivered obstetrician-gynecologists may be prescribing buprenorphine. In addition, NAS data for 2 states (Idaho and Alabama) were not available, which we did not account for in our analysis.Our study has limitations. Data were limited to obstetrician-gynecologists who treat patients enrolled in Medicaid and therefore do not include all US obstetrician-gynecologists. However, nearly 50% of births in the US are paid for by Medicaid,This study found that only 1.8% of Medicaid-claimant obstetrician-gynecologists are approved to prescribe buprenorphine. Our study contributes to the body of work describing the geographic distribution of health care clinicians who are able to prescribe buprenorphine. Given the relative benefits that buprenorphine confers toward maternal and neonatal health compared with methadone or no pharmacotherapy, as well as existing racial/ethnic and socioeconomic disparities in access to buprenorphine, these findings suggest that obstetrician-gynecologists may play a greater role in addressing the opioid epidemic beyond referring patients to OUD treatment. By becoming X-waivered, obstetrician-gynecologists could bolster the workforce of health care clinicians authorized to initiate and maintain OUD treatment.


Staphylococcus aureus (CA-MRSA) specimens collected in Western Australia (WA), and describes the changing epidemiology over this period. A total of 57 557 cases were reviewed. Annual incidence rates increased from 86.2 cases per 100 000 population to 245.6 per 100 000 population . The proportion of isolates carrying Panton–Valentine leucocidin (PVL)-associated genes increased from 3.4% to 59.8% . The emergence of PVL-positive, ‘Queensland CA-MRSA’ (ST93-IV) and ‘WA 121’ (ST5-IV) accounted for the majority of increases in CA-MRSA across the study period. It is unclear why some clones are more prolific in certain regions. In WA, CA-MRSA rates increase as indices of temperature and humidity increase after controlling for socioeconomic disadvantage. We suggest climatic conditions may contribute to transmission, along with other socio-behavioural factors. A better understanding of the ability for certain clones to form ecological niches and cause outbreaks is required.This study presents enhanced surveillance data from 2004 to 2018 for all community-associated methicillin-resistant  Staphylococcus aureus is the most commonly isolated bacterial pathogen in humans and is an important cause of skin and soft-tissue infections (SSTIs), pneumonia, septic arthritis, endocarditis, osteomyelitis, foreign-body infections and sepsis [S. aureus (MRSA) isolates are resistant to penicillins and other β-lactam antibiotics and in the past were confined mainly to health care environments [d sepsis . Methicironments . Howeverronments .In Australia, CA-MRSA infections first emerged from the northern Kimberley region in Western Australia (WA) in the early 1990s, mainly associated with Aboriginal people living in remote communities . Since tDifferent CA-MRSA strains have been demonstrated to have found ecological niches, with different regions experiencing outbreaks largely comprising different dominant strains , such asWestern Australia has adopted an aggressive approach to MRSA management, with stringent policy requirements for the screening, reporting and management of cases introduced in the 1980s .mec (SCCmec) typing which has enabled the identification of novel clones not previously reported. This study presents 15 years of enhanced surveillance data from specimens collected in WA, and describes the changing epidemiology and burden of disease over this period.Since 2003, GPTL has employed multilocus sequence typing (MLST) and staphylococcal chromosomal cassette β-lactam antibiotics than HA-MRSA clones [Phenotypically, CA-MRSA clones are generally resistant to fewer non-A clones . ClinicaA clones , 12In WA, CA-MRSA clones are frequently responsible for infections detected in the hospital setting, including those classified as nosocomial infections . Consequmec elements , and by the frequent presence of the Panton–Valentine leucocidin (PVL) lukF-PV and lukS-PV associated genes [CA-MRSA may be differentiated from HA-MRSA clones by genotypic features such as MLST, having a relatively smaller SCCed genes . Typing lukF-PV and lukS-PV PVL-associated genes mediates leukocyte and tissue destruction, and it has been suggested that its presence may cause more severe SSTIs than PVL-negative (PVL−) isolates [The protein coded by the isolates , 14. HowAlthough PVL-positive (PVL+) isolates do not appear to be related to increases in bacteraemia or mortality , a demonmec type using multiplex PCR [In WA, the classification of CA-MRSA and HA-MRSA clones is determined by a combination of the molecular analysis of the seven housekeeping genes sequence types using MLST, and the SCCplex PCR . Prior tCollection date between 1 January 2004 and 31 December 2018Persons with a WA address  at the time a sample was collectedSample was positive for a CA-MRSA clone identified by GPTLSample was identified as a clinical specimen (screening specimens excluded)Specimen was not a duplicate (specimen of the same strain collected from the same patient)Cases were extracted with the following inclusion criteria:Estimated resident population (ERP) figures from 2004 to 2017 were obtained from the Australian Bureau of Statistics for each region. Regional ERP for 2018 was estimated based on linear population growth trends for the period 2015–2017.2 and is commonly divided into eight major geographical regions. Each of these regions varies widely on a number of factors, including geography and climate, population density, proportion of Aboriginal residents, and indices of rurality and remoteness. Regional areas of the state, particularly northern and easterly regions, contain populations with some of the highest indices of socio-economic disadvantage in Australia [WA comprises approximately 2.6 million kmustralia . The popustralia .Regions were further categorised based on their climatic properties, using Bureau of Meteorology data for climate zones based on temperature and humidity .Regions were assigned to climate zones based on having a majority of regional landmass and/or population within a particular band. Zone 1  contained the northernmost Kimberley region, Zone 3  contained the northern-central Pilbara and Midwest regions, Zone 4  contained the central Wheatbelt and Goldfields regions, and Zone 5  contained the southerly Metropolitan, Southwest and Great Southern regions . Deciles95).Data analysis was performed using R version 3.5.2 . Annual incidence rates per 100 000 population were calculated. A Wilcoxon rank-sum test was used to assess the difference in continuous variables. Multivariable logistic regression was used to assess age, sex and climatic region of residence as independent risk factors for PVL+ CA-MRSA. Cases with missing data for sex and age group were deleted listwise. Negative binomial regression models were selected due to overdispersion of annual count data, and were used to estimate year-adjusted regional incidence rate ratios (IRRs) and associated 95% confidence intervals   of cases reported over the 15-year period were PVL− CA-MRSA, assessment of annual trends demonstrates the proportion of PVL+ CA-MRSA increased from 3.4% to 59.8%, comprising the majority of isolates since 2015 ( 0.0001) .Table 195 2.7–3.0). At the commencement of the monitoring period, there were some differences noted in the incidence rates of CA-MRSA in the hotter climatic zones, with significantly higher total rates in Zone 1  and Zone 3  compared with the cooler Zone 5 (reference category) in the south of the state. The differences noted at this time are entirely attributable to PVL− strains, with very few cases of PVL+ CA-MRSA (n = 58) reported within the state in 2004 . Multivariable logistic regression adjusting for collection year and IRSAD demonstrated that male sex, younger age, and residence in hotter, more humid regions were positively associated with infection with PVL+ CA-MRSA, compared to other strains  and ‘WA121’ (ST5-IV), account for the majority of increases in CA-MRSA across the study period. Proportionally, Queensland CA-MRSA accounted for 1.6% of all CA-MRSA strains in 2004; this increased to 37.9% of the total by 2018. Case numbers for this clone increased across the state, and is now the single most prolific strain in WA. As shown in The emergence of WA121 occurred in 2011 with five cases of this previously undetected clone occurring in this year. This number increased rapidly to 73 cases in 2012. Since this time, year-on-year increases in WA121 have been observed, in 2018 accounted for 740/6287 (11.8%) of all reported CA-MRSA. The same regions in which Queensland CA-MRSA has proliferated again account the majority of increase in case numbers of WA121.Greater diversity among PVL+ isolates is noted in the southerly, cooler, more densely populated regions, with South West Pacific (SWP) CA-MRSA (ST30-IV) and the PVL+ ST22-IV representing a sizeable minority within these zones. While PVL− CA-MRSA rates increased overall during this period, proportionally PVL− isolates declined from 97% of the total to 40%. This demonstrates that rather than replacement, PVL+ isolates have had an additive effect on the over rates of CA-MRSA in WA over the last 15 years.This study reports a sustained increase in clinical CA-MRSA rates in WA, with an apparent commencement of an outbreak of PVL+ MRSA in regional areas commencing 2009. Reports of increases in CA-MRSA are occurring globally, including Europe, the Asia-Pacific region and North America , 19, 20.In addition, the recent emergence of WA121 appears to follow a similar pattern as the Queensland CA-MRSA, with a sudden emergence and rapid proliferation in remote communities. Given the demonstrated ability for a newly introduced clone to add to the burden of disease in the community, the emergence of a new PVL+ clone in these regions is of particular concern. This same clone rapidly emerged in New Zealand between 2006 and 2011 [The emergence and spread of CA-MRSA, particularly in the Kimberley region, have previously been documented , 22. TheQueensland CA-MRSA has previously been implicated as a major contributor to the burden of disease in Aboriginal populations, suggesting particular genetic factors unique to this clone may have facilitated its spread in this population across Australia , 27. TheDespite numerous incursions of USA300 observed over the surveillance period, this strain has not proliferated in WA. Similarly, despite small-scale outbreaks of Queensland CA-MRSA in the UK , it has The rate of PVL+ CA-MRSA in the highly populous Zone 5 has increased, but is still lower than that of PVL− CA-MRSA. Rates of CA-MRSA in other regions that also contain areas of high disadvantage have not increased as markedly as within the state's north. This suggests that a combination of socio-behavioural and environmental factors may be reducing the ability of PVL+ CA-MRSA to proliferate within more temperate geographic locations within the state.et al. suggest a combination of temperature and humidity; namely, average weekly maximum temperatures above 33 °C and an average weekly relative humidity between 55% and 78% was associated with an increase in S. aureus-associated SSTIs [Climatic influences on MRSA SSTIs have previously been explored , althouged SSTIs . AverageFurther work linking transmission to climatic factors is recommended to better describe this phenomenon. Factors outside of the presence of PVL-associated genes and the presence of high-risk populations may help to explain the geographic differences in prolific CA-MRSA clones, and could at least partially account for the apparent ecological niche that seemingly encourages the transmission of some strains within a region, while limiting the spread of others.Limitations of this retrospective, population-based study include the inability to account for changes in the healthcare provider behaviour over the 15-year study period, in particular the propensity to send specimens for culture and typing. It is reasonable to assert that a rapid rise of specific PVL+ isolates within a region, causing SSTIs in increasing number and severity, raised the profile of CA-MRSA among local clinicians and drove up testing numbers to an extent.The observed increases in PVL− CA-MRSA observed mainly in the Kimberley region may, indeed, be largely driven by an increased propensity to test for CA-MRSA. Increased testing, however, should not have any impact on the proportion of PVL+ isolates comprising the total number of specimens, suggesting that the increase in PVL+ cases in regional WA is not entirely an artefact of increased testing, but instead represents a true outbreak within the state.Despite this limitation, the increased rates of PVL− disease, combined with an almost 50% reduction in these clones proportionally demonstrates that PVL+ clones have not replaced PVL− clones, but rather added to the burden of disease within the state. While information on individual PVL− clones is not available, the relatively minor comparative increase in rates of these clones overall suggests that it is unlikely that one or more particular outbreak clones were responsible for driving this, as was observed with PVL+ clones.An additional limitation was that Aboriginality was not available as an indicator for this dataset, prohibiting further investigation of this as a risk factor. In place of this variable, IRSAD was used as a proxy measure, to account for the relative socio-economic disadvantage prevalent in remote communities. After controlling for IRSAD in the regression model, there were still significantly increased proportions of CA-MRSA identified in the northern zones.Public health management of this current outbreak remains a challenge. The suggested propensity for CA-MRSA, particularly PVL+ clones, to spread in hotter and more humid areas, particularly among vulnerable communities, suggests WA may expect similar increases in incidence rates across a number of regions in future. Countries with climatic conditions favourable for colonisation and spread of CA-MRSA should adopt proactive mitigation strategies, particularly in areas where vulnerable populations reside.Further work to evaluate the impact of this outbreak on the healthcare system within affected regions could provide evidence of the increased burden on individual patients that results from severe SSTIs, and further quantify the economic impact to healthcare systems. Such evidence could be used as further justification for increased prevention efforts, both to halt the current outbreak and to prevent the emergence of virulent strains in future.


Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1β and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1β and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia.4 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425.VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1β and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 10Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0·58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes.Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect.UK Department of Health and the Wellcome Trust. Evidence before this studyWe searched Medline between Jan 1, 1996, and April 30, 2019, with the MeSH terms “Pneumonia”; “Pneumonia, bacterial”; “Pneumonia, Ventilator-Associated”; “Respiratory Tract Infections”; “Biomarkers”; “Protein Precursors”; and “Anti-bacterial Agents”. Although several trials investigated the role of procalcitonin in reducing antibiotic use in lower respiratory tract infections, to our knowledge, few trials have been done in patients with ventilator-associated pneumonia. A multicentre trial of a procalcitonin-guided intervention to discontinue antibiotics in patients with ventilator-associated pneumonia reported a significant improvement in antibiotic-free days at 28 days. However, the duration of antibiotics in both the intervention and the control groups of the trial were longer than the 8-day duration recommended in international guidelines. A further single-centre trial used a combination of the Clinical Pulmonary Infection Score and procalcitonin to guide antibiotic discontinuation in patients who had already completed 7 days of antibiotic therapy. Although patients in the procalcitonin group had more antibiotic-free days at 28 days versus the control group, the duration of antibiotics in both groups was longer than 8 days. These studies focused on discontinuation of antibiotics once empirical treatment was established. To our knowledge, there are no published trials in which antibiotic stewardship is based on early exclusion of ventilator-associated pneumonia.Added value of this studyTo our knowledge, VAPrapid2 is the first trial to use a validated biomarker in a cohort of patients with clinically suspected ventilator-associated pneumonia, with an aim to determine whether early exclusion of ventilator-associated pneumonia could improve antibiotic stewardship. Furthermore, our trial included a process evaluation that aimed to understand clinical behaviours and implementation of the trial protocol. This trial showed that, although the biomarker test could accurately exclude ventilator-associated pneumonia, the trial recommendation regarding antibiotic discontinuation was seldom followed by clinicians, resulting in no difference in antibiotic use between the intervention and control groups. The results of this trial highlight entrenched behaviours in antibiotic prescribing practice and barriers to adopting new, unfamiliar technologies.Implications of all the available evidencePrevious trials of procalcitonin have influenced the duration of antibiotic treatment in patients with ventilator-associated pneumonia. However, most patients with suspected ventilator-associated pneumonia do not actually have it, subjecting them to unnecessary antibiotic treatment while the true cause of respiratory compromise potentially goes untreated. Avoiding antibiotic use in such patients remains an important goal for antibiotic stewardship in intensive care units. The VAPrapid2 trial showed no influence on antibiotic prescribing practices in this patient group. Future studies should differentiate suspected from confirmed ventilator-associated pneumonia, aim to reduce antibiotics in patients who do not have confirmed infection, and dissect complex mechanisms that influence prescribing practices.Ventilator-associated pneumonia is the most common infection acquired in intensive care units (ICUs),Point prevalence studies suggest that 70% of patients in the ICU receive antibiotics.Rapid diagnostic tests with the capacity to rule out ventilator-associated pneumonia might present early opportunities to optimise antibiotic prescription and decrease antibiotic use. Among protein-based biomarkers, only a combination of low IL-1β and IL-8 concentrations in bronchoalveolar lavage fluid has been validated in a multicentre setting in suspected ventilator-associated pneumonia.10The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1β and IL-8 could improve antibiotic stewardship without compromising patient safety in suspected ventilator-associated pneumonia. In keeping with expert guidance on analysis of complex interventions,VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to the ICU with suspected ventilator-associated pneumonia. The trial was done in 24 ICUs from 17 National Health Service (NHS) hospital trusts across England, Scotland, and Northern Ireland.9/L or greater than 11 × 109/L, and purulent tracheal secretions.Patients were screened for eligibility on weekdays and included if they were aged 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Criteria for suspected ventilator-associated pneumonia were new or worsening chest radiographic (x-ray or chest CT) alveolar changes plus at least two of the following: body temperature less than 35°C or greater than 38°C, white cell count less than 4 × 102 less than 8 kPa on FiO2 greater than 0·7, positive end-expiratory pressure greater than 15 cmH2O, peak airway pressure greater than 35 cmH2O, heart rate greater than 140 beats per minute, mean arterial pressure less than 65 mm Hg, bleeding diathesis , intracranial pressure greater than 20 mm Hg, and ICU consultant considered bronchoscopy and bronchoalveolar lavage to be unsafe for the patient.Patients were excluded if they fulfilled the criteria predicting poor tolerance of bronchoscopy and bronchoalveolar lavage: PaOThe research protocol was approved by the England and Northern Ireland (13/LO/065) and Scotland (13/SS/0074) National Research Ethics Service committees, and the trial protocol has been published previously.Sealed Envelope. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Participants underwent the same clinical procedures up to the point biomarker results were returned to the clinical service for the intervention group. Therefore, there was an initial period of double-blinding until test results were communicated to clinicians. As such, clinicians and research nurses were masked until the biomarker results became available.Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit (NCTU). Randomisation was triggered by the technician receiving each patient's bronchoalveolar lavage fluid sample. The randomisation sequence was generated by the trial statistician using Investigators were asked to record a clinical opinion on the pre-test probability of ventilator-associated pneumonia in randomly assigned patients—high, medium, or low. A protocolised bronchoscopy and bronchoalveolar lavage was arranged for all randomly assigned patients using a 120 mL lavage with 0·9% saline.IL-1β and IL-8 in bronchoalveolar lavage fluid were measured by cytometric bead array using Accuri C6 flow cytometers . IL-1β and IL-8 concentrations in bronchoalveolar lavage fluid were entered into a previously derived equation for the exclusion of ventilator-associated pneumonia,4 colony forming units (CFU) per mL of bronchoalveolar lavage fluid.2 CFU/mL, 102–103 CFU/mL, 103–104 CFU/mL, 104–105 CFU/mL, and so on, allowing simple and clear demarcation of bacteria grown at 104 CFU/mL or more (ventilator-associated pneumonia) and less than 104 CFU/mL.We defined confirmed ventilator-associated pneumonia as growth of a potentially pathogenic organism of at least 10Investigators visited all ICUs before recruitment commenced, providing educational sessions on the diagnostic performance of the biomarkers and on the trial intervention. Key components of trial design were reinforced through regular communication. Additional training was done in testing laboratories with respect to laboratory processes and biomarker measurement. Before the trial commenced, clinicians were again made aware of the biomarker test and were encouraged to follow the biomarker-guided recommendations. However, antibiotic use decisions were not mandated and were at clinicians' discretion.A process evaluation was done with interviews of clinical staff and research staff  in the following three phases: pre-trial , mid-trial , and late-trial, with purposive sampling of nine sites based on pre-trial and mid-trial results . Interviews were done by LME. Further details are in the The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Antibiotic-free days were handled as an integer, with patients classified in one of eight categories .Clostridium difficile and meticillin-resistant Staphylococcus aureus) up to hospital discharge, death, or 56 days, antibiotic-resistant pathogens (resistant to two or more antibiotics) cultured up to hospital discharge, death, or 56 days, and health-care resource use calculated from length of critical care and hospital stay up to discharge, death, or 56 days. When considering outcomes at days 7, 14, and 28, antibiotics refers to all antibiotics given for treatment of infection; prophylactic antibiotics were not considered.Predefined secondary outcomes were antibiotic-free days at days 14 and 28, antibiotic days at days 7, 14, and 28, ventilator-free days at 28 days, 28-day mortality and ICU mortality, sequential organ failure assessment (SOFA) score at days 3, 7 and 14, duration of critical care (level 2 and level 3 care) and hospital stay, antibiotic-associated infections . This study is registered with ISRCTN, ISRCTN65937227, and The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics n=106; . One patS aureus . These same units also described a greater perception of risk for bronchoalveolar lavage (favouring less invasive methods) and for discontinuing antibiotics (favouring antibiotic use as the perceived lower-risk approach). For further details of the process evaluation see the In the VAPrapid2 trial, a validated test with good rule-out characteristics for ventilator-associated pneumonia did not reduce antibiotic use or improve any of our other investigated clinical outcomes. To our knowledge, this is the first trial to use biomarkers to exclude ventilator-associated pneumonia to increase confidence in early discontinuation of empirical antibiotics. Previous studies have shown proof of principle for modest antibiotic reduction in suspected ventilator-associated pneumonia using discontinuation rules.IL-1β and IL-8 fulfill the widely accepted criteria for a good exclusion test because they have a negative likelihood ratio of less than 0·1.To our knowledge, this trial is among the first in critical care to embed a process evaluation, with the aim of understanding behaviours, in accordance with expert guidance.32Inherent concern around failing to treat potential ventilator-associated pneumonia could have influenced prescribing, with fewer antibiotic-free days when pre-test probability was high. Beliefs around assumed efficacy and safety of antibiotics shape prescribing in emergency departments and presumably the motivation to avoid harm is enhanced in suspected ventilator-associated pneumonia in the ICU.In keeping with the broad spectrum of factors that determine successful introduction of complex diagnostic interventions,There are several limitations to this study. There was a higher than expected number of assay failures early in the trial. Not all centres had the assay on site, although all had access within around 90 min of sample collection. The mean time taken to return test results from bronchoalveolar lavage was more than 8 h. The study design left the decision to prescribe antibiotics with clinicians, rather than mandating stopping in accordance with test recommendations. Sites did not have a dedicated investigator who was responsible for recommending discontinuation of antibiotics. We did not systematically collect data on sites' pre-existing antibiotic stewardship policies or use of rapid diagnostics for infection, and we acknowledge the subjectivity of pre-test probability on the basis of clinician judgement. Although extrapulmonary infection was considered unlikely in eligible patients in our study, we cannot be certain that sources of infection outside the lung parenchyma  were absent. We did not collect clinical pulmonary infection scores4 CFU/mL or more is controversial.4 CFU/mL or more in bronchoalveolar lavage fluid as ventilator-associated pneumonia was based on our previous studies and large clinical trials in suspected ventilator-associated pneumonia reporting substantial growth of these organisms.Whether fungi and various bacteria traditionally considered commensals can be considered a cause of ventilator-associated pneumonia when isolated from bronchoalveolar lavage at 10Controversy also surrounds the issue of whether patients with suspected ventilator-associated pneumonia should be included in trials if antibiotics have been started or adjusted in the 3 days before microbiological sampling, because of the theoretical risk of sterilising samples taken for culture.Finally, landmark studies of blood biomarkers of infection have taken advantage of changes in diagnostic parameters over serial timepoints.In conclusion, biomarker-guided exclusion of ventilator-associated pneumonia did not reduce antibiotic use in centres that had committed to following test recommendations. Process evaluation suggested that lack of adoption of the technology and clinician behaviour had a greater influence on trial outcomes than did test performance. Antibiotic prescribing behaviours appear entrenched and recalcitrant to change. Future trials of diagnostic tests for ventilator-associated pneumonia should incorporate detailed implementation strategies informed by prior characterisation of factors that influence prescribing and diagnostic decision making.Newcastle Clinical Trials Unit.Data collected for this study will be made available  to researchers who provide a methodologically sound research proposal, to assist with achievement of aims in the approved proposal. Data will be available from the time of publication of the Article in print. Proposals should be directed to the