SUMMARY Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication nor did the DDR marks co-localize with latent episomes. Rather, a transient period of EBV-induced hyper-proliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoproteins EBNA3C was required to attenuate the EBV-induced DNA damage response We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR which is attenuated by viral latency products to induce cell immortalization.

Cell delivery to the pathological intervertebral disc (IVD) has significant therapeutic potential for enhancing IVD regeneration. The development of injectable biomaterials that retain delivered cells, promote cell survival, and maintain or promote an NP cell phenotype in vivo remains a significant challenge. Previous studies have demonstrated NP cell – laminin interactions in the nucleus pulposus (NP) region of the IVD that promote cell attachment and biosynthesis. These findings suggest that incorporating laminin ligands into carriers for cell delivery may be beneficial for promoting NP cell survival and phenotype. Here, an injectable, laminin-111 functionalized poly(ethylene glycol) (PEG-LM111) hydrogel was developed as a biomaterial carrier for cell delivery to the IVD. We evaluated the mechanical properties of the PEG-LM111 hydrogel, and its ability to retain delivered cells in the IVD space. Gelation occurred in approximately 20 minutes without an initiator, with dynamic shear moduli in the range of 0.9 – 1.4 kPa. Primary NP cell retention in cultured IVD explants was significantly higher over 14 days when cells were delivered within a PEG-LM111 carrier, as compared to cells in liquid suspension. Together, these results suggest this injectable laminin-functionalized biomaterial may be an easy to use carrier for delivering cells to the IVD.

➢ Osteochondral lesions of the talus remain difficult pathological entities to treat and require the utilization of a combination of conventional radiographs, computed tomographic scans, and magnetic resonance images to determine osseous involvement. Along with the size of the lesion, these characteristics will dictate the treatment required to obtain a satisfactory clinical result.➢ Operative treatment should be reserved for patients who have mechanical symptoms following an acute osteochondral lesion of the talus or who are not satisfied with the result after 3 to 6 months of nonoperative treatment.➢ The gold standard of operative treatment for lesions measuring <1.5 cm2 remains microfracture. Repair, replacement, or regenerative procedures should be considered for patients with refractory lesions or larger lesions.

Epstein-Barr virus (EBV) infection of primary B cellsleads to the outgrowth of indefinitely proliferating lymphoblastoid cell lines (LCLs). However, the efficiency of immortalization is less than 10% of infected cells. We hypothesize that a robust innate tumor suppressor response prevents long-term outgrowth of the majority of infected cells. In this study we identify the DNA damage response (DDR) as a major component of this response. EBV infection of primary B cells activated hallmarks of the DDR including phosphorylated ATM, Chk2, g-H2AX, and 53BP1 foci. DDR activation was not due to lytic viral DNA replication nor did its marks co-localize with latent viral episomes. Rather, EBV induced a period of hyper-proliferation early after infection responsible for DDR activation. Microarray data supported the transient activation and subsequent attenuation of proliferation and DDR-associated mRNAs during LCL outgrowth. Importantly, activation of this pathway suppressed transformation as small molecule antagonism of the DNA damage responsive kinases ATM and Chk2 increased EBV transformation efficiency. Thus, we propose a model whereby EBV infection initially drives aberrant cellular DNA replication activating an anti-proliferative DNA damage response. Long-term outgrowth depends on attenuation of this hyper-proliferative signal through full latency III gene expression. AcknowledgementsThis article has been published as part of Infectious

Objective To determine the utility of silk fibroin (SF) microparticles as sustained release vehicles for intra-articular delivery. Design SF formulations were varied to generate microparticle drug carriers that were characterized in vitro for their physical properties, release kinetics for a conjugated fluorophore (Cy7), and in vivo for intra-articular retention time using live-animal, fluorescence in vivo imaging. Results SF microparticle carriers were spherical in shape and ranged from 598 nm to 21.5 μm in diameter. SF microparticles provided for sustained release of Cy7 in vitro, with only 10% of the initial load released over 7 days. Upon intra-articular injection in rat knee joints, the SF microparticles were associated with an intra-articular fluorescence decay half-life of 43.3 hours, greatly increasing the joint residence over that for an equivalent concentration of SF-Cy7 in solution form. The SF microparticles also increase the localization of dye within the joint cavity as determined by image analysis of fluorescent gradients, significantly reducing distribution of the Cy7 to neighboring tissue as compared to SF-Cy7 in free solution. Conclusion Silk microparticles act to provide for localized and sustained delivery of loaded small molecules following intra-articular injection, and may be an attractive strategy for delivering small molecule drugs for the treatment of arthritis.

To examine prognostic factors that influence complications after hip fracture surgery. To summarise proposed underlying mechanisms for their influence. MethodsWe reported according to Preferred Reporting Items for Systematic Review and Meta-Analysis Scoping Review extension. We searched MEDLINE, Embase, CINAHL, AgeLine, Cochrane Library, and reference lists of retrieved studies for studies of prognostic factor/s of postoperative in-hospital medical complication/s among patients 50 years and older treated surgically for non-pathological closed hip fracture, published in English January 2008 -January 2018. We excluded studies of surgery type or in-hospital medications. Screening was duplicated by two independent reviewers. One reviewer completed extraction with accuracy checks by a second. We summarised extent, nature, and proposed underlying mechanisms for prognostic factors of complications narratively and in a dependency graph. ResultsWe identified 44 prognostic factors of in-hospital complications after hip fracture surgery from 56 studies. Of these, we identified 7 patient factors-dehydration, anaemia, hypotension, heart rate variability, pressure risk, nutrition, indwelling catheter use; and 7 process factors-time to surgery, anaesthetic type, transfusion strategy, orthopaedic versus geriatric/comanaged care, and multidisciplinary care pathway, potentially modifiable during index hospitalisation. We identified underlying mechanisms for 15 of 44 factors. The reported association between 12 prognostic factors and complications was inconsistent across studies. ConclusionsMost factors were reported by one study with no proposed underlying mechanism for their influence. Where reported by more than one study, there was inconsistency in reported associations and the conceptualisation of complications differed, limiting comparison across studies. It is therefore not possible to be certain whether intervening on these factors would reduce the rate of complications after hip fracture surgery.

Posterior wall acetabulum fractures typically result from high-energy mechanisms and can be associated with various orthopaedic and nonorthopaedic injuries. They range from isolated simple patterns to multifragmentary with or without marginal impaction. Determination of hip stability, which can depend on fragment location, size, and displacement, directs management. Although important in the assessment of posterior wall fractures, CT is unreliable when used to determine stability. The dynamic fluoroscopic examination under anesthesia (EUA) is the benchmark in assessment of hip stability, and fractures deemed stable by EUA have good radiographic and functional outcomes. In fractures that meet surgical criteria, accurate joint reduction guides outcomes. Joint débridement, identification and elevation of impaction, and adjunctive fixation of posterosuperior and peripheral rim fragments along with standard buttress plate fixation are critical. Complications of the fracture and surgical fixation include sciatic nerve injury, posttraumatic osteoarthritis, osteonecrosis of the femoral head, and heterotopic ossification. Although accuracy of joint reduction is paramount for successful results, other factors out of the surgeon's control such as comminution, femoral head lesions, and dislocation contribute to poor outcomes. Even with anatomic restoration of the joint surface, good clinical outcomes are not guaranteed and residual functional deficits can be expected.

* Giant cell tumors are the most common tumors found in the epiphyses of the long bones.* Chondroblastomas classically present in the epiphyses of the long bones abutting the physis as a lytic-appearing lesion.* Clear cell chondrosarcomas are tumors that classically present in the epiphysis in patients who are in their third to fifth decade of life.