Search

Background Open fractures of the major long bones are complex limb‐threatening injuries that are predisposed to deep infection. Treatment includes antibiotics and surgery to debride the wound, stabilise the fracture and reconstruct any soft tissue defect to enable infection‐free bone repair. There is a need to assess the effect of timing and duration of antibiotic administration and timing and staging of surgical interventions to optimise outcomes. Objectives To assess the effects (risks and benefits) of the timing of antibiotic administration, wound debridement and the stages of surgical interventions in managing people with open long bone fractures of the upper and lower limbs. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trial registers in February 2021. We also searched conference proceedings and reference lists of included studies. Selection criteria We included randomised controlled trials (RCTs) or quasi‐RCTs that recruited adults with open fractures of the major long bones, comparing: 1) timings of prophylactic antibiotic treatment, 2) duration of prophylactic antibiotic treatment, 3) timing of wound debridement following injury or 4) timing of the stages of reconstructive surgery. Data collection and analysis We used standard methodological procedures expected by Cochrane. We aimed to collect data for the following outcomes: limb function, health‐related quality of life (HRQoL), deep surgical site infection, delayed or non‐union, adverse events (in the short‐ and long‐term course of recovery), and resource‐related outcomes. Main results We included three RCTs of 613 randomised participants with 617 open fractures. Studies were conducted in medical and trauma centres in the USA and Kenya. Where reported, there was a higher proportion of men and a mean age of participants between 30 and 34 years old. Fractures were in the upper and lower limbs in one study, and were tibia fractures in two studies; where reported, these were the result of high‐energy trauma such as road traffic accidents. No studies compared the timing of antibiotic treatment or wound debridement. Duration of prophylactic antibiotic treatment (1 study, 77 participants available for analysis) One study compared antibiotic treatment for 24 hours with antibiotic treatment for five days. We are very uncertain about the effects of different durations of antibiotic treatment on superficial infections (risk ratio (RR) 1.19, 95% CI 0.49 to 2.87, favours 5 day treatment; 1 study, 77 participants); this was very low‐certainty evidence derived from one small study with unclear and high risks of bias, and with an imprecise effect estimate. This study reported no other review outcomes. Reconstructive surgery: timing of the stages of surgery (2 studies, 458 participants available for analysis) Two studies compared the timing of wound closure, which was completed immediately or delayed. In one study, the mean time of delay was 5.9 days; in the other study, the time of delay was not reported. We are very uncertain about the effects of different timings of wound closure on deep infections (RR 0.82, 95% CI 0.37 to 1.80, favours immediate closure; 2 studies, 458 participants), delayed union or non‐union (RR 1.13, 95% CI 0.83 to 1.55, favours delayed closure; 1 study, 387 participants), or superficial infections (RR 6.45, 95% CI 0.35 to 120.43, favours delayed closure; 1 study, 71 participants); this was very low‐certainty evidence. We downgraded the certainty of the evidence for very serious risks of bias because both studies had unclear and high risks of bias. We also downgraded for serious imprecision because effect estimates were imprecise, including the possibility of benefits as well as harms, and very serious imprecision when the data were derived from single small study. These studies reported no other review outcomes. Authors' conclusions We could not determine the risks and benefits of different treatment protocols for open long bone fractures because the evidence was very uncertain for the two comparisons and we did not find any studies addressing the other possible comparisons. Well‐designed randomised trials with adequate power are needed to guide surgical and antibiotic treatment of open fractures, particularly with regard to timing and duration of antibiotic administration and timing and staging of surgery.

Significance While stem cell therapy has become the standard of care for hematological disorders, challenges remain for the treatment of solid organ injuries. Targeting endogenous cells would overcome many hurdles associated with exogenous stem cell therapy. Alarmins are released upon tissue damage, and here we describe how upregulation of a physiological pathway by exogenous administration of a single dose of HMGB1, either locally or systemically, promotes tissue repair by targeting endogenous stem cells. We show that HMGB1 complexed with CXCL12 transitions stem cells that express CXCR4 from G0 to GAlert. These primed cells rapidly respond to appropriate activating factors released upon injury. HMGB1 promotes healing even if administered 2 wk before injury, thereby expanding its translational benefit for diverse clinical scenarios., A major discovery of recent decades has been the existence of stem cells and their potential to repair many, if not most, tissues. With the aging population, many attempts have been made to use exogenous stem cells to promote tissue repair, so far with limited success. An alternative approach, which may be more effective and far less costly, is to promote tissue regeneration by targeting endogenous stem cells. However, ways of enhancing endogenous stem cell function remain poorly defined. Injury leads to the release of danger signals which are known to modulate the immune response, but their role in stem cell-mediated repair in vivo remains to be clarified. Here we show that high mobility group box 1 (HMGB1) is released following fracture in both humans and mice, forms a heterocomplex with CXCL12, and acts via CXCR4 to accelerate skeletal, hematopoietic, and muscle regeneration in vivo. Pretreatment with HMGB1 2 wk before injury also accelerated tissue regeneration, indicating an acquired proregenerative signature. HMGB1 led to sustained increase in cell cycling in vivo, and using Hmgb1−/− mice we identified the underlying mechanism as the transition of multiple quiescent stem cells from G0 to GAlert. HMGB1 also transitions human stem and progenitor cells to GAlert. Therefore, exogenous HMGB1 may benefit patients in many clinical scenarios, including trauma, chemotherapy, and elective surgery.

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

To compare the clinico-pathologic prognostic factors and survival of younger vs older women diagnosed with epithelial ovarian cancer. Demographic, clinico-pathologic, treatment, and surgery information were obtained from patients with ovarian cancer from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001 and analysed using Kaplan-Meier estimates. Of 28 165 patients, 400 were 60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4664 (40.2%), and 3643 (22.5%) had stage I-II disease, respectively (P