Win Ratio Analyses of Piperacillin-Tazobactam Versus Meropenem for Ceftriaxone-Nonsusceptible Escherichia coli or Klebsiella pneumoniae Bloodstream Infections: Post Hoc Insights From the MERINO Trial.

BACKGROUND: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. METHODS: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. RESULTS: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). CONCLUSIONS: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.

Rapid diagnostic tests and antimicrobial stewardship programs for the management of bloodstream infection: What is their relative contribution to improving clinical outcomes? A systematic review and network meta-analysis.

BACKGROUND: Evidence about the clinical impact of rapid diagnostic tests (RDT) for the diagnosis of bloodstream infections is limited, and whether RDT are superior to conventional blood cultures (BC) embedded within antimicrobial stewardship programs (ASP) is unknown. METHODS: We performed network meta-analyses (NMA) using results from studies of patients with bloodstream infection with the aim of comparing the clinical impact of RDT (applied on positive BC broth or whole blood) to conventional BC, both assessed with and without ASP with respect to mortality, length of stay (LOS) and time to optimal therapy (TOT). RESULTS: Eighty-eight papers were selected, including 25,682 patient encounters. There was an appreciable amount of statistical heterogeneity within each meta-analysis. The NMA showed a significant reduction in mortality associated with the use of RDT + ASP vs BC alone (OR 0.72, 95%CI 0.59, 0.87) and with the use of RDT + ASP vs BC + ASP (OR 0.78 95%CI 0.63, 0.96). No benefit in survival was found associated with the use of RDT alone nor with BC + ASP compared to BC alone. A reduction in LOS was associated with RDT + ASP vs BC alone (0.91, 95%CI 0.84, 0.98) while no difference in LOS was shown between any other groups. A reduced TOT was shown when RDT + ASP was compared to BC alone (-29 h, 95%CI -35, -23), BC + ASP (-18 h, 95%CI -27, -10) and to RDT alone (-12 h, 95%CI -20, -3). CONCLUSION: The use of RDT + ASP may lead to a survival benefit even when introduced in settings already adopting effective ASP in association with conventional BC.

Persistence of Detectable Pathogens by Culture-Independent Systems (T2 Magnetic Resonance) in Patients With Bloodstream Infection: Prognostic Role and Possible Clinical Implications.

BACKGROUND: Persistent Staphylococcus aureus bacteremia is associated with metastatic infection and adverse outcomes, whereas gram-negative bacteremia is normally transient and shorter course therapy is increasingly advocated for affected patients. Whether the prolonged detection of pathogen DNA in blood by culture-independent systems could have prognostic value and guide management decisions is unknown. METHODS: We performed a multicenter, prospective, observational study on 102 patients with bloodstream infection (BSI) to compare time to bloodstream clearance according to T2 magnetic resonance and blood cultures over a 4-day follow-up. We also explored the association between duration of detectable pathogens according to T2 magnetic resonance (magnetic resonance-DNAemia [MR-DNAemia]) and clinical outcomes. RESULTS: Time to bloodstream clearance according to T2 magnetic resonance was significantly longer than blood culture clearance (HR, .54; 95% CI, .39-.75) and did not differ according to the causative pathogen (P = .5). Each additional day of MR-DNAemia increased the odds of persistent infection (defined as metastatic infection or delayed source control) both in the overall population (OR, 1.98; 95% CI, 1.45-2.70) and in S. aureus (OR, 1.92; 95% CI, 1.12-3.29) and gram-negative bacteremia (OR, 2.21; 95% CI, 1.35-3.60). MR-DNAemia duration was also associated with no improvement in Sequential Organ Failure Assessment score at day 7 from infection onset (OR, 1.76; 95% CI, 1.21-2.56). CONCLUSIONS: T2 magnetic resonance may help diagnose BSI in patients on antimicrobials with negative blood cultures as well as to identify patients with metastatic infection, source control failure, or adverse short-term outcome. Future studies may inform its usefulness within the setting of antimicrobial stewardship programs.

Characterization of gram-negative bloodstream infections in hospitalised Australian children and their clinical outcomes.

BACKGROUND: Gram-negative bloodstream infections (GNBSI) more commonly occur in children with comorbidities and are increasingly associated with antimicrobial resistance. There are few large studies of GNBSI in children that relate the clinical presentation, pathogen characteristics and outcomes. METHODS: A 3-year prospective study of GNBSI in children aged <18 years was conducted in five Australian children's hospitals between 2019-2021. The clinical characteristics, disease severity and outcomes were recorded. Causative pathogens underwent antibiotic susceptibility testing and whole genome sequencing. RESULTS: There were 931 GNBSI episodes involving 818 children. Median age was 3 years (IQR 0.6-8.5). 576/931 episodes (62%) were community onset though 661/931 (71%) occurred in children with comorbidities and a central venous catheter (CVC) was present in 558/931 (60%). CVC (145/931) and urinary tract (149/931) were the most common sources (16% each). 100/931 (11%) children required Intensive Care Unit (ICU) admission and a further 11% (105/931) developed GNBSI in ICU. 659/927 (71%) isolates were Enterobacterales of which 22% (138/630) were third generation cephalosporin resistant (3GCR). Extended spectrum beta-lactamase genes (ESBL) were confirmed in 65/138 (47%) 3GCR-Enterobacterales. Most common ESBL genes were blaCTX-M-15 (34/94, 36%) and blaSHV-12 (10/94, 11%). There were 48 deaths overall and 30-day in-hospital mortality was 3% (32/931). Infections with 3GCR Enterobacterales were independently associated with higher mortality (adjusted OR 3.2, 95%CI 1.6-6.4). CONCLUSION: GNBSI in children are frequently healthcare-associated and affect children under 5 years. Infections with 3GCR Enterobacterales were associated with worse outcomes. These findings will inform optimal management guidelines and help prioritise future antimicrobial clinical trials.

Hearing loss in Australian First Nations children at 6-monthly assessments from age 12 to 36 months: Secondary outcomes from randomised controlled trials of novel pneumococcal conjugate vaccine schedules.

BACKGROUND: In Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations. METHODS AND FINDINGS: In 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size. CONCLUSIONS: In this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01735084 and NCT01174849.

Which reference equation should we use for interpreting spirometry values for First Nations Australians? A cross-sectional study.

OBJECTIVES: To evaluate the suitability of the Global Lung Function Initiative (GLI)-2012 other/mixed and GLI-2022 global reference equations for evaluating the respiratory capacity of First Nations Australians. DESIGN, SETTING: Cross-sectional study; analysis of spirometry data collected by three prospective studies in Queensland, the Northern Territory, and Western Australia between March 2015 and December 2022. PARTICIPANTS: Opportunistically recruited First Nations participants in the Indigenous Respiratory Reference Values study (Queensland, Northern Territory; age, 3-25 years; 18 March 2015 - 24 November 2017), the Healthy Indigenous Lung Function Testing in Adults study (Queensland, Northern Territory; 18 years or older; 14 August 2019 - 15 December 2022) and the Many Healthy Lungs study (Western Australia; five years or older; 10 October 2018 - 7 November 2021). MAIN OUTCOME MEASURES: Goodness of fit to spirometry data for each GLI reference equation, based on mean Z-score and its standard deviation, and proportions of participants with respiratory parameter values within 1.64 Z-scores of the mean value. RESULTS: Acceptable and repeatable forced expiratory volume in the first second (FEV1) values were available for 2700 First Nations participants in the three trials; 1467 were classified as healthy and included in our analysis (1062 children, 405 adults). Their median age was 12 years (interquartile range, 9-19 years; range, 3-91 years), 768 (52%) were female, and 1013 were tested in rural or remote areas (69%). Acceptable and repeatable forced vital capacity (FVC) values were available for 1294 of the healthy participants (88%). The GLI-2012 other/mixed and GLI-2022 global equations provided good fits to the spirometry data; the race-neutral GLI-2022 global equation better accounted for the influence of ageing on FEV1 and FVC, and of height on FVC. Using the GLI-2012 other/mixed reference equation and after adjusting for age, sex, and height, mean FEV1 (estimated difference, -0.34; 95% confidence interval [CI], -0.46 to -0.22) and FVC Z-scores (estimated difference, -0.45; 95% CI, -0.59 to -0.32) were lower for rural or remote than for urban participants, but their mean FEV1/FVC Z-score was higher (estimated difference, 0.14; 95% CI, 0.03-0.25). CONCLUSION: The normal spirometry values of healthy First Nations Australians may be substantially higher than previously reported. Until more spirometry data are available for people in urban areas, the race-neutral GLI-2022 global or the GLI-2012 other/mixed reference equations can be used when assessing the respiratory function of First Nations Australians.

Patient outcome quality indicators for older persons in acute care: original development data using interRAI AC-CGA.

BACKGROUND: A range of strategies are available that can improve the outcomes of older persons particularly in relation to basic activities of daily living during and after an acute care (AC) episode. This paper outlines the original development of outcome-oriented quality indicators (QIs) in relation to common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. METHODS: Design QIs were developed using evidence from literature, expert opinion, field study data and a formal voting process. A systematic literature review of literature identified existing QIs (there were no outcome QIs) and evidence of interventions that improve older persons' outcomes in AC. Preliminary indicators were developed by two expert panels following consideration of the evidence. After analysis of the data from field testing (indicator prevalence, variability across sites), panel meetings refined the QIs prior to a formal voting process. SETTING: Data was collected in nine Australian general medical wards. PARTICIPANTS: Patients aged 70 years and over, consented within 24 h of admission to the AC ward. MEASUREMENTS: The interRAI Acute Care - Comprehensive Geriatric Assessment (interRAI AC-CGA) was administered at admission and discharge; a daily risk assessment in hospital; 28-day phone follow-up and chart audit. RESULTS: Ten outcome QIs were established which focused on common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. CONCLUSION: Ten outcome QIs were developed. These QIs can be used to identify areas where specific action will lead to improvements in the quality of care delivered to older persons in hospital.

Neurological examination at 32-weeks postmenstrual age predicts 12-month cognitive outcomes in very preterm-born infants.

BACKGROUND: To determine the diagnostic accuracy of Hammersmith Neonatal Neurological Examination (HNNE) at 30-32 weeks postmenstrual age (PMA, 'Early') and term equivalent age (TEA) in infants born <31 weeks PMA to predict cognitive outcomes at 12 months corrected age (CA). METHODS: Prospective cohort study of 119 infants (73 males; median 28.4 weeks gestational age at birth) who underwent Early and TEA HNNE. At 12 months CA, 104 participants completed Bayley Scales of Infant and Toddler Development, 3rd Edition, (Bayley-III). Optimum cut-off points for each HNNE subscale were determined to establish diagnostic accuracy for predicting adverse cognitive outcomes on the Bayley-III Cognitive Composite Scale (≤85). RESULTS: The best diagnostic accuracy for HNNE total score at 30-32 weeks PMA predicting cognitive impairment occurred at cut-off ≤16.7 (sensitivity (Se) = 71%, specificity (Sp) = 51%). The Abnormal Signs subscale demonstrated the best balance of sensitivity/specificity combination (Se = 71%, Sp = 71%; cut-off ≤1.5). For HNNE at TEA, the total score at cut-off ≤24.5 had Se = 71% and Sp = 47% for predicting cognitive impairment. The Tone Patterns subscale demonstrated the strongest diagnostic accuracy at TEA (Se = 71%, Sp = 63%; cut-off ≤3). CONCLUSIONS: Early and TEA HNNE demonstrated moderate diagnostic accuracy for cognitive outcomes at 12-months CA in infants born <31 weeks gestational age. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; Trial Registration Number: ACTRN12613000280707; web address of trial: http://www.ANZCTR.org.au/ACTRN12613000280707.aspx . IMPACT: Early Hammersmith Neonatal Neurological Examination (HNNE) assessment at 30-32 weeks postmenstrual age has moderate diagnostic accuracy for cognitive outcomes at 12 months corrected age in infants born <31 weeks gestation. Early HNNE at 30-32 weeks has stronger predictive validity than HNNE at term equivalent age. Early HNNE may provide an early marker for risk-stratification to optimise the planning of post-discharge support and follow-up services for infants born preterm.

Development of social functioning in children with cerebral palsy: A longitudinal study.

AIM: To describe the development of social function in children with cerebral palsy (CP) classified in all levels of the Communication Function Classification System (CFCS). METHOD: This prospective, longitudinal population-based cohort study recruited children with CP born in Queensland, Australia. Social functioning was measured using the Pediatric Evaluation of Disability Inventory (PEDI) social function domain at 2 years, 2 years 6 months, 3 years, 4 years, and 5 years, and the PEDI Computer Adaptive Test (PEDI-CAT) social/cognitive domain at 8 to 12 years. RESULTS: Seventy-four children provided 356 observations. PEDI-CAT social/cognitive scaled scores at 8 to 12 years were (mean [SD] n) CFCS level I, 68.6 (2.7) 45; CFCS level II, 64.0 (3.4) 10; CFCS level III, 63.5 (3.7) 4; CFCS level IV, 56.8 (5.0) 9; CFCS level V, 47.2 (5.8) 6. Scores within expected range for age (not less than 2 SD below mean) at 8 to 12 years were achieved by 35 (78%) children in CFCS level I and four (14%) in CFCS levels II to V. Forty-nine per cent of children scored at least two standard deviations below the population mean on a proxy measure of fluid intelligence. Intellectual impairment was associated with lower PEDI-CAT social/cognitive scaled scores in univariable analysis (ß = -8.3, 95% confidence interval - 10.91 to -5.63; p < 0.001) but had a smaller effect when modelled together with CFCS. INTERPRETATION: Social function attained by 8 to 12 years of age was strongly related to level of communication function (CFCS). The small number of children classified in CFCS levels II to V necessitates caution when viewing these individual CFCS level trajectories. WHAT THIS PAPER ADDS: There is a strong relation between social functioning and Communication Function Classification System (CFCS) levels. At 8 to 12 years, 35 out of 45 children in CFCS level I met social functioning age expectations. Twenty-five out of 29 in CFCS levels II to V had social functioning below that expected for age. CFCS and age were more strongly associated with development of social functioning than Gross Motor Function Classification System or Manual Ability Classification System and age.

Diagnostic accuracy of the Hammersmith Neonatal Neurological Examination in predicting motor outcome at 12 months for infants born very preterm.

AIM: To evaluate the predictive validity of the Hammersmith Neonatal Neurological Examination (HNNE) performed early (at 32 weeks postmenstrual age) and at term-equivalent age (TEA) for 12-month motor outcomes in infants born very preterm. METHOD: This was a diagnostic study using data from a prospective birth cohort. A total of 104 infants born preterm at less than 31 weeks gestational age (males n = 61; mean = 28 weeks 1 day [SD 1 week 6 days], range 23 weeks 1 day-30 weeks 6 days) underwent HNNE early and at TEA, which were scored by comparison with term data. Motor outcomes at 12 months corrected age were determined using the Bayley Scales of Infant and Toddler Development, Third Edition (scores ≤85). Cut-off points were determined using receiver operating characteristic curves. RESULTS: Sixteen (15%) infants born preterm had motor impairment at 12 months corrected age. The HNNE total score cut-off points with the best combination of sensitivity and specificity at early and TEA assessments were 15.2 or lower (sensitivity 77%, 95% confidence interval [CI] = 46%-95%; specificity 74%, 95% CI = 63%-83%) and 23.5 or lower (sensitivity 67%, 95% CI = 38%-88%; specificity 66%, 95% CI = 54%-76%) respectively. The most predictive subscale at the early assessment was reflexes (sensitivity 86%, 95% CI = 57%-98%; specificity 62%, 95% CI = 51%-72%; cut-off point ≤3); at TEA, it was spontaneous movements (sensitivity 73%, 95% CI = 45%-92%; specificity 60%, 95% CI = 48%-70%; cut-off point ≤2). INTERPRETATION: The HNNE provides moderate predictive accuracy for motor outcome at 12 months corrected age in infants born very preterm. Although modest at both time points, early assessment had stronger predictive ability for motor outcomes than TEA when scored using term data, highlighting the value of performing the HNNE earlier in the neonatal period. Performing HNNE earlier may assist risk stratification when planning follow-up services.

A prospective, observational study of frailty, quality of life and dialysis in older people with advanced chronic kidney disease.

BACKGROUND: Frailty is prevalent in older people with chronic kidney disease (CKD) and robust evidence supporting the benefit of dialysis in this setting is lacking. We aimed to measure frailty and quality of life (QOL) longitudinally in older people with advanced CKD and assess the impact of dialysis initiation on frailty, QOL and mortality. METHODS: Outpatients aged ≥65 with an eGFR ≤ 20ml/minute/1.73m2 were enrolled in a prospective observational study and followed up four years later. Frailty status was measured using a Frailty Index (FI), and QOL was evaluated using the EuroQol 5D-5L instrument. Mortality and dialysis status were determined through inspection of electronic records. RESULTS: Ninety-eight participants were enrolled. Between enrolment and follow-up, 36% of participants commenced dialysis and 59% died. Frailty prevalence increased from 47% at baseline to 86% at follow-up (change in median FI = 0.22, p < 0.001). Initiating dialysis was not significantly associated with change in FI. QOL declined from baseline to follow-up (mean EQ-5D-5L visual analogue score of 70 vs 63, p = 0.034), though commencing dialysis was associated with less decline in QOL. Each 0.1 increment in baseline FI was associated with 59% increased mortality hazard (HR = 1.59, 95%CI = 1.20 to 2.12, p = 0.001), and commencing dialysis was associated with 59% reduction in mortality hazard (HR = 0.41, 95%CI = 0.20 to 0.87, p = 0.020) irrespective of baseline FI. CONCLUSIONS: Frailty increased substantially over four years, and higher baseline frailty was associated with greater mortality. Commencing dialysis did not affect the trajectory of FI but positively influenced the trajectory of QOL from baseline to follow-up. Within the limitations of small sample size, our data suggests that frail participants received similar survival benefit from dialysis as non-frail participants.

Effect of Active Motor Learning Interventions on Gross Motor Function and Mobility in Children Aged 2 to 6 Years With Bilateral Cerebral Palsy: A Systematic Review and Meta-analysis.

PURPOSE: The purpose of this systematic review is to identify evidence-based interventions to promote active motor learning in children aged 2 to 6 years with bilateral cerebral palsy. SUMMARY OF KEY POINTS: Seven randomized clinical trials of active motor learning interventions targeting gross motor function and mobility were included. Two studies compared context-focused therapy to child-focused therapy. Five studies compared active motor therapy to usual care. Context-focused therapy, child-focused therapy, and active motor therapy were comparable to usual care to improve functional mobility and gross motor function. CONCLUSIONS AND RECOMMENDATIONS FOR CLINICAL PRACTICE: There are limited active intervention studies targeting gross motor function for young children with bilateral cerebral palsy. The authors recommend consideration of the clinical good practice guidelines, dosage parameters, and improved reporting methods when implementing active motor learning interventions targeting gross motor function and mobility for children with cerebral palsy.

Event-free survival after radical prostatectomy according to prostate-specific membrane antigen-positron emission tomography and European Association of Urology biochemical recurrence risk groups.

OBJECTIVE: To assess European Association of Urology (EAU) risk groups for biochemical recurrence (BCR) of prostate cancer relative to prostate-specific membrane antigen-positron emission tomography (PSMA-PET) status and oncological outcomes. PATIENTS AND METHODS: A retrospective analysis of a study that incorporated PSMA-PET for men with BCR after radical prostatectomy (RP) was undertaken. EAU risk groups were considered relative to clinical variables, PSMA-PET findings, and deployment of salvage radiotherapy (SRT). The primary oncological outcome was event-free survival (EFS) and this was analysed relative to clinical and imaging variables. An 'event' occurred if prostate-specific antigen (PSA) level rose >0.2 ng/mL above nadir or additional therapies were introduced. RESULTS: A total of 137 patients were included, most of whom had EAU high-risk disease (76%) and/or low PSA levels (80% <0.5 ng/mL) at the time of PSMA-PET. EAU risk group was not associated with regional nodal/distant metastasis on PSMA-PET. Regional nodal/distant metastasis on PSMA PET (compared to negative/local recurrence: hazard ratio [HR] 2.2; P = 0.002) and SRT use (vs no SRT: HR 0.44; P = 0.004) were associated with EFS. EAU high-risk status was not significantly associated with worse EFS (HR 1.7, P = 0.12) compared to EAU low-risk status. Among patients who received SRT, both regional/distant metastasis on PSMA-PET (HR 3.1; P < 0.001) and EAU high-risk status (HR 2.9; P = 0.04) were independently associated with worse EFS, which was driven by patients in the EAU high-risk group with regional/distant metastases (38%; HR 3.1, P = 0.001). CONCLUSIONS: In patients with post-RP BCR, PSMA-PET findings and receipt of SRT predicted EFS. In patients receiving SRT, PSMA status combined with EAU risk grouping was most predictive of EFS. These findings suggest that the EAU risk groups could be improved with the addition of PSMA-PET.

Characteristics and outcomes of carbapenemase harbouring carbapenem-resistant Klebsiella spp. bloodstream infections: a multicentre prospective cohort study in an OXA-48 endemic setting.

A prospective, multicentre observational cohort study of carbapenem-resistant Klebsiella spp. (CRK) bloodstream infections was conducted in Turkey from June 2018 to June 2019. One hundred eighty-seven patients were recruited. Single OXA-48-like carbapenemases predominated (75%), followed by OXA-48-like/NDM coproducers (16%). OXA-232 constituted 31% of all OXA-48-like carbapenemases and was mainly carried on ST2096. Thirty-day mortality was 44% overall and 51% for ST2096. In the multivariate cox regression analysis, SOFA score and immunosuppression were significant predictors of 30-day mortality and ST2096 had a non-significant effect. All OXA-48-like producers remained susceptible to ceftazidime-avibactam.

Evaluation of low-volume plasma sampling for the analysis of meropenem in clinical samples.

Reducing the volume of blood sampled from neonatal or paediatric patients is important to facilitate research in a group that is under-represented in clinical studies. Not all patients have a cannula available for blood sampling, meaning there are real advantages in obtaining a blood microsample by skin prick. In this study, the results obtained from both capillary microsamples (CMS) and a microfluidic (MF)-CMS by skin prick are compared to conventional plasma sampled from an arterial catheter in a clinical bridging study. Six critically ill patients receiving meropenem were included with the incurred sample reanalysis test meeting the acceptance criteria for both CMS (n = 24 samples) and MF-CMS (n = 20 samples). Bland-Altman plots comparing MF-CMS to conventional arterial blood sampling revealed a difference of - 12.7 ± 22.1% (mean ± standard deviation (SD), and comparing CMS to conventional arterial blood sampling a difference of - 3.4 ± 17.0%. At - 12.7%, the bias between MF-CMS and conventional sampling is greater than the bias found with CMS, although within the limit of acceptability for analytical accuracy (that being ± 15%). Samples collected by skin prick and using CMS produced meropenem concentrations that were comparable to those obtained from conventional arterial catheter sampling. CMS samples were found to be stable when stored in the capillary tube for 24 h at 5 °C or for 4 h at room temperature.

Patient and pathological predictors of management strategy for malignant polyps following polypectomy: a systematic review and meta-analysis.

PURPOSE: Malignant polyps present a treatment dilemma for clinicians and patients. This meta-analysis sought to identify the factors that predicted the management strategy for patients diagnosed with a malignant polyp. METHODS: A literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Collaboration prognostic studies guidelines. Reports from 1985 onwards were included, data on patient and pathological factors were extracted and random effects meta-analysis models were used. RESULTS: Fifteen studies were included. Seven studies evaluated lymphovascular invasion (LVI). The odds of surgery were significantly higher in malignant polyps with LVI (OR 2.20, 95% CI 1.36-3.55). Ten studies revealed the odds of surgery were significantly higher with positive polypectomy margins (OR 8.09, 95% CI 4.88-13.40). Tumour differentiation was compared in eight studies. There were significantly lower odds of surgery in malignant polyps with well/moderate differentiation compared with poor differentiation (OR 0.31, 95% CI 0.21-0.46). There were non-significant trends favouring surgical resection in younger patients, males and Haggitt 4/Kikuchi Sm3 lesions. There was considerable heterogeneity in the meta-analyses for the variables age, gender, polyp morphology and Haggitt/Kikuchi level (I2 > 75%). CONCLUSION: This meta-analysis has demonstrated that LVI, positive polypectomy resection margins, and poor tumour differentiation significantly predict malignant polypectomy patients who underwent subsequent surgery. Age and gender were important factors predicting management, but not consistently across studies, whilst polyp morphology and Haggitt/Kikuchi levels did not significantly predict the management strategy. Further research may assist in understanding the management preferences.

How does the Canadian Acute Respiratory Illness and Flu Scale relate to other scales in pediatric asthma exacerbations?

OBJECTIVES: In children with asthma exacerbations, we evaluated the relationship between Canadian Acute Respiratory Illness and Flu Scale (CARIFS) scores and (a) Asthma Diary Scale (ADS) scores for 14 days; (b) Pediatric Asthma Caregiver's Quality of Life (QoL) Questionnaire (PACQLQ) scores on days 1, 7 and 14; (c) viral detection. We hypothesized that in children with acute asthma, CARIFS scores correlate with ADS and PACQLQ scores over time and that viruses have little impact on CARIFS scores. METHODS: In children aged 2-16 years who presented with acute asthma to the Emergency Departments of 2 hospitals, we documented the clinical history, examination, asthma severity at baseline and on presentation. Eighteen respiratory pathogens were determined by PCR on nasopharyngeal aspirate (NPA) collected on recruitment. The parent(s) recorded their child's daily CARIFS and ADS and weekly PACQLQ for 14 days. We used Spearman's correlation to relate the scores of 108 children. RESULTS: CARIFS scores correlated well with ADS scores throughout 14 days (rs ranged 0.30-0.67). CARIFS and PACQLQ scores correlated -0.28, -0.14 and -0.44 on days 1, 7 and 14 respectively. There was no significant difference in CARIFS scores between children whose NPAs were PCR virus-positive or -negative over 14 days. CONCLUSIONS: CARIFS and ADS scores correlated well as a disease severity measure during the recovery period in children with acute asthma and this was not influenced by the virus state. The ADS may be used as an alternative in selected situations. The CARIFS reflects different aspects to acute asthma severity and QoL.

Development of gross motor capacity and mobility performance in children with cerebral palsy: a longitudinal study.

AIM: To describe development of gross motor capacity and mobility performance in children with cerebral palsy. METHOD: This longitudinal cohort study measured gross motor capacity with the Gross Motor Function Measure and mobility performance with the Pediatric Evaluation of Disability Inventory (PEDI) between 18 months and 5 years, and the PEDI - Computer Adaptive Test (PEDI-CAT) between 8 years and 12 years. Longitudinal analyses used mixed-effects regression modelling with interaction between age and Gross Motor Function Classification System (GMFCS). Stability of GMFCS levels over time was measured using agreement. RESULTS: Two hundred and twenty-two children provided 871 observations (median 4 observations, range 1-7). Children classified in GMFCS level I improved in both capacity and performance until 8 to 12 years. Children classified in GMFCS levels II and III continued to develop mobility performance after gross motor capacity had plateaued at 5 years. Children classified in GMFCS level IV plateaued at 5 years in capacity and performance. Children classified in GMFCS level V showed no changes in capacity or performance between 18 months and 8 to 12 years. Stability of GMFCS levels was 73%. INTERPRETATION: Change in mobility performance over time somewhat reflected gross motor capacity trajectories. Continued improvement in mobility performance after plateau of gross motor capacity for children classified in GMFCS levels II and III suggests importance of other personal or environmental factors.

Program for the Education and Enrichment of Relational Skills for adolescents with an acquired brain injury: A randomized controlled trial.

AIM: To test the efficacy of a group social skills intervention on social functioning in adolescents with a brain injury. METHOD: Thirty-six adolescents (mean age 14y, SD 1y 8mo, age range 12y 1mo-16y 3mo; 17 females) with acquired brain injury (ABI; ≥12mo postintervention; n=19) or cerebral palsy (n=17) were randomly allocated to the Program for the Education in Enrichment of Relational Skills (PEERS) or usual care. The primary outcome was the Social Skills Improvement System-Rating Scales (SSIS-RS). Secondary outcomes were scores derived from the Test of Adolescent Social Skills Knowledge-Revised (TASSK-R), Social Responsiveness Scale, Second Edition, and Quality of Socialization Questionnaire. Between-group differences postintervention and at the 26-week retention time point were compared using linear mixed modelling for continuous outcomes and Poisson regression for count data. RESULTS: There were no between-group differences on the primary outcome (SSIS-RS). Regarding the secondary outcomes, the PEERS-exposed group achieved significantly greater improvements on the TASSK-R (mean difference [MD]=6.8, 95% confidence interval [CI]=4.8-8.8, p<0.001), which were maintained at the 26-week retention time point (MD=8.1, 95% CI=6.0-10.2, p<0.001). PEERS was also associated with a significant increase in parent-reported invited get-togethers at 26 weeks (incidence rate ratio=4.0, 95% CI=1.0-16.0, p=0.05). INTERPRETATION: Adolescents with brain injury who completed the PEERS learned and retained social knowledge and increased social participation.

Systemic therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer.

BACKGROUND: Adjuvant aromatase inhibitors (AI) improve survival compared to tamoxifen in postmenopausal women with hormone receptor-positive stage I to III breast cancer. In approximately half of these women, AI are associated with aromatase inhibitor-induced musculoskeletal symptoms (AIMSS), often described as symmetrical pain and soreness in the joints, musculoskeletal pain and joint stiffness. AIMSS may have significant and prolonged impact on women's quality of life. AIMSS reduces adherence to AI therapy in up to a half of women, potentially compromising breast cancer outcomes. Differing systemic therapies have been investigated for the prevention and treatment of AIMSS, but the effectiveness of these therapies remains unclear. OBJECTIVES: To assess the effects of systemic therapies on the prevention or management of AIMSS in women with stage I to III hormone receptor-positive breast cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, WHO International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov registries to September 2020 and the Cochrane Breast Cancer Group (CBCG) Specialised Register to March 2021.  SELECTION CRITERIA: We included all randomised controlled trials that compared systemic therapies to a comparator arm. Systemic therapy interventions included all pharmacological therapies, dietary supplements, and complementary and alternative medicines (CAM). All comparator arms were allowed including placebo or standard of care (or both) with analgesia alone. Published and non-peer-reviewed studies were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, extracted data, and assessed risk of bias and certainty of the evidence using the GRADE approach. Outcomes assessed were pain, stiffness, grip strength, safety data, discontinuation of AI, health-related quality of life (HRQoL), breast cancer-specific quality of life (BCS-QoL), incidence of AIMSS, breast cancer-specific survival (BCSS) and overall survival (OS). For continuous outcomes, we used vote-counting by reporting how many studies reported a clinically significant benefit within the confidence intervals (CI) of the mean difference (MD) between treatment arms, as determined by the minimal clinically importance difference (MCID) for that outcome scale. For dichotomous outcomes, we reported outcomes as a risk ratio (RR) with 95% CI. MAIN RESULTS: We included 17 studies with 2034 randomised participants. Four studies assessed systemic therapies for the prevention of AIMSS and 13 studies investigated treatment of AIMSS. Due to the variation in systemic therapy studies, including pharmacological, and CAM, or unavailable data, meta-analysis was limited, and only two trials were combined for meta-analysis. The certainty of evidence for all outcomes was either low or very low certainty. Prevention studies The evidence is very uncertain about the effect of systemic therapies on pain (from baseline to the end of the intervention; 2 studies, 183 women). The two studies, investigating vitamin D and omega-3 fatty acids, showed a treatment effect with 95% CIs that did not include an MCID for pain. Systemic therapies may have little to no effect on grip strength (RR 1.08, 95% CI 0.37 to 3.17; 1 study, 137 women) or on women continuing to take their AI (RR 0.16, 95% 0.01 to 2.99; 1 study, 147 women). The evidence suggests little to no effect on HRQoL and BCS-QoL from baseline to the end of intervention (the same single study; 44 women, both quality of life outcomes showed a treatment effect with 95% CIs that did include an MCID). The evidence is very uncertain for outcomes assessing incidence of AIMSS (RR 0.82, 95% CI 0.63 to 1.06; 2 studies, 240 women) and the safety of systemic therapies (4 studies, 344 women; very low-certainty evidence). One study had a US Food and Drug Administration alert issued for the intervention (cyclo-oxygenase-2 inhibitor) during the study, but there were no serious adverse events in this or any study. There were no data on stiffness, BCSS or OS. Treatment studies The evidence is very uncertain about the effect of systemic therapies on pain from baseline to the end of intervention in the treatment of AIMSS (10 studies, 1099 women). Four studies showed an MCID in pain scores which fell within the 95% CI of the measured effect (vitamin D, bionic tiger bone, Yi Shen Jian Gu granules, calcitonin). Six studies showed a treatment effect with 95% CI that did not include an MCID (vitamin D, testosterone, omega-3 fatty acids, duloxetine, emu oil, cat's claw).  The evidence was very uncertain for the outcomes of change in stiffness (4 studies, 295 women), HRQoL (3 studies, 208 women) and BCS-QoL (2 studies, 147 women) from baseline to the end of intervention. The evidence suggests systemic therapies may have little to no effect on grip strength (1 study, 107 women). The evidence is very uncertain about the safety of systemic therapies (10 studies, 1250 women). There were no grade four/five adverse events reported in any of the studies. The study of duloxetine reported more all-grade adverse events in this treatment group than comparator group. There were no data on the incidence of AIMSS, the number of women continuing to take AI, BCCS or OS from the treatment studies. AUTHORS' CONCLUSIONS: AIMSS are chronic and complex symptoms with a significant impact on women with early breast cancer taking AI. To date, evidence for safe and effective systemic therapies for prevention or treatment of AIMSS has been minimal. Although this review identified 17 studies with 2034 randomised participants, the review was challenging due to the heterogeneous systemic therapy interventions and study methodologies, and the unavailability of certain trial data. Meta-analysis was thus limited and findings of the review were inconclusive. Further research is recommended into systemic therapy for AIMSS, including high-quality adequately powered RCT, comprehensive descriptions of the intervention/placebo, and robust definitions of the condition and the outcomes being studied.