Republication of "Ankle Fracture-Dislocations: A Review".

Ankle fractures are common musculoskeletal injuries that may result in tibiotalar joint dislocations. Ankle fracture-dislocations occur via similar mechanisms as ankle fractures, although the persistence or magnitude of the deforming force is sufficient to disrupt any remaining bony or soft-tissue stability. Ankle fracture-dislocations likely represent distinct clinical entities, as the pathology, management, and patient outcomes following these injuries differ from those seen in more common ankle fractures without dislocation. Ankle fracture-dislocations have higher rates of concomitant injury including open fractures, chondral lesions, and intra-articular loose bodies. Long-term outcomes in ankle fracture-dislocations are worse than ankle fractures without dislocation. Higher rates of posttraumatic osteoarthritis and chronic pain have also been reported. In this review, we discuss the current literature regarding the history, management, and outcomes of ankle-fracture dislocations and highlight the need for future study.

Does the frailty index predict discharge disposition and length of stay at the hospital and rehabilitation facilities?

INTRODUCTION: Many geriatric hip fracture patients utilize significant healthcare resources and require an extensive recovery period after surgery. There is an increasing awareness that measuring frailty in geriatric patients may be useful in predicting mortality and perioperative complications and may be useful in helping guide treatment decisions. The primary purpose of the study is to investigate whether the frailty index predicts discharge disposition from the hospital and discharge facility and length of stay. METHODS: In this retrospective cohort study, patients aged 65 years and older presenting to a level 1 trauma center with a hip fracture and a calculated frailty index were eligible for inclusion. The primary outcome was discharge disposition. Secondary outcomes were hospital and discharge facility length of stay, 90-day hospital mortality and readmissions, and return to home. RESULTS: A total of 313 patients were included. The frailty index was a robust predictor of discharge to a skilled nursing facility (OR 1.440 per 0.1 point increase). Patients with a higher frailty index were at higher risk of 90-day mortality and less likely to return to home at the end of follow-up. There was a very weak correlation between the frailty index and hospital length of stay (ρ=0.30) and rehab length of stay (ρ=0.26). CONCLUSION: The frailty index can be used to predict discharge destination from both the hospital and rehabilitation facility, 90-day mortality, and return to home after rehabilitation. In this study, the frailty index had a very weak correlation with length of stay in the hospital and in discharge destination. The frailty index can be used to help guide medical decision making, goals of care discussions, and to determine which patients benefit from intensive rehabilitation.

Structural Basis of TLR2/TLR1 Activation by the Synthetic Agonist Diprovocim.

Diprovocim is a recently discovered exceptionally potent, synthetic small molecule agonist of TLR2/TLR1 and has shown significant adjuvant activity in anticancer vaccination against murine melanoma. Since Diprovocim bears no structural similarity to the canonical lipopeptide ligands of TLR2/TLR1, we investigated how Diprovocim interacts with TLR2/TLR1 through in vitro biophysical, structural, and computational approaches. We found that Diprovocim induced the formation of TLR2/TLR1 heterodimers as well as TLR2 homodimers in vitro. We determined the crystal structure of Diprovocim in a complex with a TLR2 ectodomain, which revealed, unexpectedly, two Diprovocim molecules bound to the ligand binding pocket formed between two TLR2 ectodomains. Extensive hydrophobic interactions and a hydrogen-bonding network between the protein and Diprovocim molecules are observed within the defined ligand binding pocket and likely underlie the high potency of Diprovocim. Our work shed first light into the activation mechanism of TLR2/TLR1 by a noncanonical agonist. The structural information obtained here may be exploited to manipulate TLR2/TLR1-dependent signaling.

Anatomy, Classification, and Management of Ankle Fractures Involving the Posterior Malleolar Fragment: A Literature Review.

The posterior malleolar fragment is frequently involved in rotational ankle fractures, but diagnosis and definitive management remains controversial. Ankle fractures with a posterior malleolar component that are not identified and treated in a timely manner may contribute significantly to future comorbidities, including continued pain, instability, and the development of arthritis. This article highlights the anatomic features of posterior malleolar ankle fractures, the classification schemes used, and discusses the various nonsurgical and surgical methods currently used. LEVEL OF EVIDENCE: Level V, expert opinion.

Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists.

A screen conducted with nearly 100000 compounds and a surrogate functional assay for stimulation of an immune response that measured the release of TNF-α from treated human THP-1 myeloid cells differentiated along the macrophage line led to the discovery of the diprovocims. Unique to these efforts and of special interest, the screening leads for this new class of activators of an immune response came from a compound library designed to promote cell-surface receptor dimerization. Subsequent comprehensive structure-activity relationship studies improved the potency 800-fold over that of the screening leads, providing diprovocim-1 and diprovocim-2. The diprovocims act by inducing cell-surface toll-like receptor (TLR)-2 dimerization and activation with TLR1 (TLR1/TLR2 agonist), bear no structural similarity to any known natural or synthetic TLR agonist, and are easy to prepare and synthetically modify, and selected members are active in both human and murine systems. The most potent diprovocim (3, diprovocim-1) elicits full agonist activity at extraordinarily low concentrations (EC50 = 110 pM) in human THP-1 cells, being more potent than the naturally derived TLR1/TLR2 agonist Pam3CSK4 or any other known small molecule TLR agonist.

Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice.

Successful cancer immunotherapy entails activation of innate immune receptors to promote dendritic cell (DC) maturation, antigen presentation, up-regulation of costimulatory molecules, and cytokine secretion, leading to activation of tumor antigen-specific cytotoxic T lymphocytes (CTLs). Here we screened a synthetic library of 100,000 compounds for innate immune activators using TNF production by THP-1 cells as a readout. We identified and optimized a potent human and mouse Toll-like receptor (TLR)1/TLR2 agonist, Diprovocim, which exhibited an EC50 of 110 pM in human THP-1 cells and 1.3 nM in primary mouse peritoneal macrophages. In mice, Diprovocim-adjuvanted ovalbumin immunization promoted antigen-specific humoral and CTL responses and synergized with anti-PD-L1 treatment to inhibit tumor growth, generating long-term antitumor memory, curing or prolonging survival of mice engrafted with the murine melanoma B16-OVA. Diprovocim induced greater frequencies of tumor-infiltrating leukocytes than alum, of which CD8 T cells were necessary for the antitumor effect of immunization plus anti-PD-L1 treatment.

Cozen's deformity: resolved by guided growth.

Proximal tibial metaphyseal fractures in children can lead to progressive and symptomatic tibial valgus. Corrective osteotomy has been abandoned, due to frequent complications, including recurrent valgus deformity. While spontaneous remodelling has been reported, this is not predictable. For children with persistent deformities, we have resorted to guided growth of the tibia. We present 19 patients who were successfully treated with guided growth, tethering the proximal medial physis. There were ten boys and nine girls, ranging in age from two to 13.6 years at the time of intervention. The mean follow-up from injury was 7.3 years. We documented the intermalleolar distance, mechanical axis deviation (by zone), medial proximal tibial angle (MPTA), and leg length discrepancy. Removal of the plate, or more recently, the metaphyseal screw, was undertaken upon normalization of the mechanical axis. Including the four patients who have undergone repeat tethering for recurrent valgus (one patient-twice), we are effectively reviewing 24 Cozen's phenomena, making this the largest series reported in the literature. Correction of the mechanical axis and the proximal medial tibial angle was achieved in all but one patient. Limb length inequality at follow-up ranged from 0.1 to 1.5 cm, with a mean of 0.5 cm. There have been five recurrences in four patients to date; four corrected with repeat tethering and one is pending. Two patients developed significant over correction because of parental failure to pursue timely follow-up. Both have corrected to neutral with lateral tibial physeal tethering. Ten patients have attained skeletal maturity and required no further treatment. The remaining nine patients will be followed until maturity. Guided growth is an excellent choice for the management of post-traumatic tibial valgus. Our rationale for restricting medial overgrowth is twofold: (1) to restore the MPTA and (2) to reduce the length discrepancy due to tibial overgrowth caused by the fracture. Recognizing the potential for recurrent deformity following implant removal, our standard practice now includes removal of just the metaphyseal screw and subsequent reinsertion, in the event of rebound valgus deformity.Level of evidence Therapeutic IV, retrospective series/no control cohort.

An unusual variant of perilunate fracture dislocations.

Trans-scaphoid, trans-radial styloid, trans-triquetral perilunate fracture dislocations are rare. We describe a 19-year-old male who suffered this injury after crashing his bicycle. He underwent open reduction internal fixation and percutaneous pinning. Scaphoid union was achieved at 8 weeks. Near complete range of painless motion was achieved by 4 months.

Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists.

Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.

TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS.

Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity to the established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3 activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, inducing an active receptor complex similar to that induced by lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.

Positive communication paradigm decreases early recurrence in clubfoot treatment.

BACKGROUND: The Ponseti method has become the treatment standard for idiopathic clubfoot. Deformity recurrence is most commonly attributed to premature abandonment of the requisite abduction orthosis. A study in 2009 from our center revealed a high rate of deformity recurrence in our patient population. It was surmised that the importance of bracing to maintain correction had not been adequately communicated to some families, especially Native Americans. As a result, the principal investigator developed a different communication protocol for parents of infants. METHODS: All children treated for clubfoot at the University of New Mexico Carrie Tingley Hospital, Albuquerque, NM, from 2008 to 2010 were reviewed. They were compared with a historical control group from this institution, the subjects of the 2009 study, and were analyzed for the rate of recurrence and Pirani score improvement. RESULTS: Our study cohort comprised 69 infants (104 clubfeet), all of whom were treated with the new communication style. The recurrence rate for the new communication paradigm was 2.88% compared with 18.2% in the control group (P<0.001). The Pirani score improvement was 4.0 in the treatment group compared with 3.5 in the control group (P=0.001). Native American recurrence was zero in the treatment group and 41% in the control group (P=0.011). CONCLUSIONS: A positive, rather than a negative communication style, emphasis on the brace as the most important aspect of treatment, and a more culturally sensitive family education paradigm, resulted in a lower rate of deformity recurrence when treating children with clubfeet using the Ponseti method. LEVEL OF EVIDENCE: Level III.

Total synthesis of lepadiformine alkaloids using N-Boc α-amino nitriles as trianion synthons.

Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent reductive lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski-Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.

Fully substituted carbon centers by diastereoselective spirocyclization: stereoselective synthesis of (+)-lepadiformine C.

Reductive lithiation of N-Boc alpha-amino nitriles generated alpha-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A(1,3)-strain effect that biases the conformation of the radical. In cyclohexane rings with alpha-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with alpha-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The alpha-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.

Reductive spiroannulation of nitriles with secondary electrophiles.

The scope of reductive decyanation and spiroannulation reactions has been expanded to include secondary electrophiles for potentially useful transformations. Secondary phosphates and chlorides, as well as terminal epoxides, cyclize in a stereospecific fashion. Both endo and exo modes of cyclization were observed with terminal epoxides.