Prognostic significance of ethnicity and age in advanced stage epithelial ovarian cancer: An NRG oncology/gynecologic oncology group study

BACKGROUND: Age and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy. METHODS: Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants. RESULTS: One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16-1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26-0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59-0.90). CONCLUSIONS: Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups

Transfusion therapy in paediatric trauma patients: a review of the literature

Haemorrhage is a leading cause of death in paediatric trauma patients. Predefined massive transfusion protocols (MTP) have the potential to significantly reduce mortality by treating haemorrhagic shock and coagulopathy, in adhering to the principles of haemostatic resuscitation with rapid administration of balanced ratios of packed red blood cells (RBC), fresh frozen plasma (FFP) and platelets (PLT). Because of their substantial physiological reserve, initial vital signs may not be good predictors of early haemorrhage in paediatric patients. Determining the triggers for MTP activation in paediatric trauma patients is challenging, and the optimal blood product ratio that will increase survival in massively bleeding paediatric trauma patients has yet to be determined. To date, only a few small descriptive studies and case reports have investigated the use of predefined MTP in paediatric trauma patients. MTP with increased FFP or PLT to RBC ratios combined with viscoelastic haemostatic assay (VHA) guided haemostatic resuscitation have not yet been tested in paediatric populations but based on results from adult trauma patients, this therapeutic approach seems promising. Considering the high prevalence of early coagulopathy in paediatric trauma patients, immediate identification and implementation of VHA-directed treatment of traumatic coagulopathy could ensure faster haemostasis and thereby, potentially, reduce bleeding as well as the total transfusion requirements and further improve outcome in paediatric trauma patients. Prospective randomized trials investigating this therapeutic approach in paediatric trauma patients are highly warranted

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Prevalence of osteochondral lesions in the fetlock and hock joints of Standardbred horses that survived bacterial infection before 6 months of age

Abstract Background Young Standardbred horses frequently develop fragments in joints. Some fragments represent osteochondrosis; others are considered developmental, but it is uncertain whether they result from preceding osteochondrosis. Osteochondrosis occurs as a consequence of failure of the cartilage canal blood supply and ischaemic chondronecrosis. In heritably predisposed foals, failure was associated with incorporation of vessels into bone. However, bacterial vascular failure was also recently documented in foals suffering spontaneous infections, proving that bacteria can cause osteochondral lesions in foals up to 150 days old. The aim was to determine prevalence of fetlock and hock lesions at screening age in Standardbred horses that survived infections before 6 months of age, and compare this to prevalence reported in the literature. Methods The material consisted of 28 Standardbred horses; 17 males and 11 females that presented and were diagnosed clinically with bacterial infections from 1 to 150 days of age (average: 41.3 days). A screening set of 8 radiographic projections was available from all 28 horses at 7–85 months of age (average: 23.6 months). Lesion prevalence was compared to three previously reported Standardbred cohorts. Results Osteochondral lesions were detected in one or more joints of 19/28 horses (67.9%); in the fetlock joint of 14/28 horses (50%) and the hock joint of 11/28 horses (39.3%). These prevalences were ≥ 2 x higher than the corresponding prevalences in the comparison cohorts, and statistically significantly so in 5:6 comparisons (p-values from < 0.00001 to 0.01). In the sepsis cohort, there were an average of 2.3 affected joints and 2.5 lesions per affected horse, whereas there in the one comparable literature cohort were an average of 1.5 affected joints and 1.7 lesions per affected horse. Conclusions Standardbred horses that survived bacterial infections before 6 months of age had more osteochondral lesions than literature comparison cohorts at screening age. The implication was that some of the lesions in this group were caused by bacteria. It may become necessary to develop methods for differentiating between acquired, septic and aseptic, heritably predisposed lesions

Additional file 1: of Prevalence of osteochondral lesions in the fetlock and hock joints of Standardbred horses that survived bacterial infection before 6 months of age

Table S1. Literature search. (DOCX 27 kb

The DnaK Chaperone System Buffers the Fitness Cost of Antibiotic Resistance Mutations in Mycobacteria

AMR is a global problem, especially for TB. Here, we show that mycobacterial chaperones support AMR in M. smegmatis , a nonpathogenic model of M. tuberculosis , the causative agent of TB. </jats:p