In patients with combined clavicle and multiple rib fractures, does fracture fixation of the clavicle improve clinical outcomes? A multicenter prospective cohort study of 232 patients

BACKGROUND Clavicle and rib fractures are often sustained concomitantly. The combination of injuries may result in decreased stability of the chest wall, making these patients prone to (respiratory) complications and prolonged hospitalization. This study aimed to assess whether adding chest wall stability by performing clavicle fixation improves clinical outcomes in patients with concurrent clavicle and rib fractures. METHODS A prospective multicenter study was performed including all adult patients admitted between January 2018 and March 2021 with concurrent ipsilateral clavicle and rib fractures. Patients treated operatively versus nonoperatively for their clavicle fracture were matched using propensity score matching. The primary outcome was hospital length of stay (HLOS). Secondary outcomes were intensive care unit length of stay, duration of mechanical ventilation, pain, complications, and quality of life at 6 weeks and 12 months of follow-up. RESULTS In total, 232 patients with concomitant ipsilateral clavicle and rib fractures were included. Fifty-two patients (22%) underwent operative treatment of which 39 could be adequately matched to 39 nonoperatively treated patients. No association was observed between clavicle plate fixation and HLOS (mean difference, 2.3 days; 95% confidence interval, -2.1 to 6.8; p = 0.301) or any secondary endpoint. Eight of the 180 nonoperatively treated patients (4%) had a symptomatic nonunion, for which 5 underwent secondary clavicle fixation. CONCLUSION We found no evidence that, in patients with combined clavicle and multiple rib fractures, plate fixation of the clavicle reduces HLOS, pain, or (pulmonary) complications, nor that it improves quality of life. STUDY TYPE Therapeutic/Care Management; Level III

Non-operative vs. operative treatment for multiple rib fractures after blunt thoracic trauma: a multicenter prospective cohort study

Background: Patients with multiple rib fractures without a clinical flail chest are increasingly being treated with rib fixation; however, high-quality evidence to support this development is lacking. Methods: We conducted a prospective multicenter observational study comparing rib fixation to non-operative treatment in all patients aged 18 years and older with computed tomography confirmed multiple rib fractures without a clinical flail chest. Three centers performed rib fixation as standard of care. For adequate comparison, the other three centers performed only non-operative treatment. As such clinical equipoise formed the basis for the comparison in this study. Patients were matched using propensity score matching. Results: In total 927 patients with multiple rib fractures were included. In the three hospitals that performed rib fixation, 80 (14%) out of 591 patients underwent rib fixation. From the nonoperative centers, on average 71 patients were adequately matched to 71 rib fixation patients after propensity score matching. Rib fixation was associated with an increase in hospital length of stay (HLOS) of 4.9 days (95%CI 0.8–9.1, p = 0.02) and a decrease in quality of life (QoL) measured by the EQ5D questionnaire at 1 year of 0.1 (95% CI − 0.2–0.0, p = 0.035) compared to non-operative treatment. A subgroup analysis of patients who received operative care within 72 h showed a similar decrease in QoL. Up to 22 patients (28%) who underwent surgery experienced implant-related irritation. Conclusions: We found no benefits and only detrimental effects associated with rib fixation. Based on these results, we do not recommend rib fixation as the standard of care for patients with multiple rib fractures. Trial registration: Registered in the Netherlands Trial Register NTR6833 on 13/11/2017

Nonoperative treatment of multiple rib fractures, the results to beat: International multicenter prospective cohort study among 845 patients

BACKGROUND Optimal treatment (i.e., nonoperative or operative) for patients with multiple rib fractures remains debated. Studies that compare treatments are rationalized by the alleged poor outcomes of nonoperative treatment. METHODS The aim of this prospective international multicenter cohort study (between January 2018 and March 2021) with 1-year follow-up, was to report contemporary outcomes of nonoperatively treated patients with multiple rib fractures. Including 845 patients with three or more rib fractures. Primary outcome was in-hospital mortality. Secondary outcomes included hospital length of stay (HLOS), (pulmonary) complications, and quality of life. RESULTS Mean age was 57.7 ± 17.0 years, median Injury Severity Score was 17 (13-22) and the median number of rib fractures was 6 (4-8). In-hospital mortality rate was 1.5% (n = 13), 112 (13.3%) patients had pneumonia and four (0.5%) patients developed a symptomatic nonunion. The median HLOS was 7 days (4-13 days), and median intensive care unit length of stay was 2 days (1-5 days). Mean 5-Level Quality of Life Questionnaire index value was 0.83 ± 0.18 1 year after trauma. Polytrauma patients had a median HLOS of 10 days (6-18 days), a pneumonia rate of 17.6% (n = 77) and mortality rate of 1.7% (n = 7). Elderly patients (≥65 years) had a median HLOS of 9 days (5-15 days), a pneumonia rate of 19.7% (n = 57) and mortality rate of 4.1% (n = 12). CONCLUSION Overall, nonoperative treatment of patients with multiple rib fractures shows low mortality and morbidity rate and good quality of life after 1 year. Future studies evaluating the benefit of operative stabilization should use contemporary outcomes to establish the therapeutic margin of rib fixation. LEVEL OF EVIDENCE Therapeutic/Care Management; Level III

A mRNA landscape of bovine embryos after standard and MAPK-inhibited culture conditions: a comparative analysis.

BACKGROUND: Genes and signalling pathways involved in pluripotency have been studied extensively in mouse and human pre-implantation embryos and embryonic stem (ES) cells. The unsuccessful attempts to generate ES cell lines from other species including cattle suggests that other genes and pathways are involved in maintaining pluripotency in these species. To investigate which genes are involved in bovine pluripotency, expression profiles were generated from morula, blastocyst, trophectoderm and inner cell mass (ICM) samples using microarray analysis. As MAPK inhibition can increase the NANOG/GATA6 ratio in the inner cell mass, additionally blastocysts were cultured in the presence of a MAPK inhibitor and changes in gene expression in the inner cell mass were analysed. RESULTS: Between morula and blastocyst 3,774 genes were differentially expressed and the largest differences were found in blastocyst up-regulated genes. Gene ontology (GO) analysis shows lipid metabolic process as the term most enriched with genes expressed at higher levels in blastocysts. Genes with higher expression levels in morulae were enriched in the RNA processing GO term. Of the 497 differentially expressed genes comparing ICM and TE, the expression of NANOG, SOX2 and POU5F1 was increased in the ICM confirming their evolutionary preserved role in pluripotency. Several genes implicated to be involved in differentiation or fate determination were also expressed at higher levels in the ICM. Genes expressed at higher levels in the ICM were enriched in the RNA splicing and regulation of gene expression GO term. Although NANOG expression was elevated upon MAPK inhibition, SOX2 and POU5F1 expression showed little increase. Expression of other genes in the MAPK pathway including DUSP4 and SPRY4, or influenced by MAPK inhibition such as IFNT, was down-regulated. CONCLUSION: The data obtained from the microarray studies provide further insight in gene expression during bovine embryonic development. They show an expression profile in pluripotent cells that indicates a pluripotent, epiblast-like state. The inability to culture ICM cells as stem cells in the presence of an inhibitor of MAPK activity together with the reported data indicates that MAPK inhibition alone is not sufficient to maintain a pluripotent character in bovine cells

A Barcode Screen for Epigenetic Regulators Reveals a Role for the NuB4/HAT-B Histone Acetyltransferase Complex in Histone Turnover

Dynamic modification of histone proteins plays a key role in regulating gene expression. However, histones themselves can also be dynamic, which potentially affects the stability of histone modifications. To determine the molecular mechanisms of histone turnover, we developed a parallel screening method for epigenetic regulators by analyzing chromatin states on DNA barcodes. Histone turnover was quantified by employing a genetic pulse-chase technique called RITE, which was combined with chromatin immunoprecipitation and high-throughput sequencing. In this screen, the NuB4/HAT-B complex, containing the conserved type B histone acetyltransferase Hat1, was found to promote histone turnover. Unexpectedly, the three members of this complex could be functionally separated from each other as well as from the known interacting factor and histone chaperone Asf1. Thus, systematic and direct interrogation of chromatin structure on DNA barcodes can lead to the discovery of genes and pathways involved in chromatin modification and dynamics

Investigating the relationships between unfavourable habitual sleep and metabolomic traits:evidence from multi-cohort multivariable regression and Mendelian randomization analyses

BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.</p

Proteins with Complex Architecture as Potential Targets for Drug Design: A Case Study of Mycobacterium tuberculosis

Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only