Stress Injuries in the Athlete.

Stress fractures are a common injury that present in athletes because of the high intensity and repetitive nature of many sports. These injuries require a high index of suspicion in the treating clinician to allow for timely management. Though most low-risk fractures heal well with conservative management, high-risk stress fractures as well as any fracture in the elite athlete may warrant surgical intervention as well as an augmented treatment and rehabilitation regimen.

High-Throughput Binder Confirmation Using Affinity Selection Mass Spectrometry.

Affinity selection mass spectrometry (AS-MS) was recently applied to a new high-throughput binder confirmation (HTBC) platform. The HTBC-AS-MS platform can assess target engagement for hundreds of chemical series per target and is used at GSK to prioritize synthesis decisions for follow-up organic synthesis of DNA-encoded library technology (ELT) hits.

Discovery of 1'-(1-phenylcyclopropane-carbonyl)-3H-spiro[isobenzofuran-1,3'-pyrrolidin]-3-one as a novel steroid mimetic scaffold for the potent and tissue-specific inhibition of 11ß-HSD1 using a scaffold-hopping approach.

11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a three-point pharmacophore for 11ß-HSD1 that was utilized to design a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of INCB13739. Clinical evaluation of INCB13739 confirmed for the first time that tissue-specific inhibition of 11ß-HSD1 in patients with type 2 diabetes mellitus was efficacious in controlling glucose levels and reducing cardiovascular risk factors.

DNA-Encoded Library Hit Confirmation: Bridging the Gap Between On-DNA and Off-DNA Chemistry.

DNA-encoded library (DEL) technology is a powerful platform for hit identification in academia and the pharmaceutical industry. When conducting off-DNA resynthesis hit confirmation after affinity selection, PCR/sequencing, and data analysis, one typically assumes a "one-to-one" relationship between the DNA tag and the chemical structure of the attached small-molecule it encodes. Because library synthesis often yields a mixture, this approximation increases the risk of overlooking positive discoveries and valuable information. To address this issue, we apply a library synthesis "recipe" strategy for on-DNA resynthesis using a cleavable linker, followed by direct affinity selection mass spectrometry (AS-MS) evaluation and identification of binder(s) from the released small-molecule mixture. We validate and showcase this approach employing the receptor-interacting-protein kinase 2 (RIP2) DEL campaign. We also designed and developed two cleavable linkers to enable this method, a photocleavable linker (nitrophenyl-based) and acid-labile linker (tetrahydropyranyl ether). The strategy provides an effective means of hit identification and rapid determination of key active component(s) of the mixture.

In Vivo Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.

First Metatarsophalangeal Joint Space Area Decreases Within 1 Month After Implantation of a Polyvinyl Alcohol Hydrogel Implant: A Retrospective Radiographic Case Series.

In 2016, the U.S. Food and Drug Administration approved the first and only polyvinyl alcohol hydrogel implant for the treatment of hallux rigidus. The implant functions as a bumper to maintain first metatarsophalangeal joint space to prevent contact of the phalangeal base with the first metatarsal head. Short-term and intermediate outcomes with this implant have reported positive outcomes with no radiographic outcomes of implant wear or subsidence. We performed a retrospective radiographic review of 27 consecutive patients who received the implant and measured preoperative and postoperative joint space area (JSA). We found a significant improvement in JSA (p < .001) between the preoperative JSA and JSA at the first postoperative visit at 1 to 2 weeks. We also found a significant decrease in JSA (p < .001) between the first postoperative visit and the second postoperative visit at 5 to 12 weeks. This information could have further implications for implant design as well as how we can better achieve functional improvements in the first metatarsophalangeal joint in patients with hallux rigidus.

Lateral Column Lengthening for Revision Triple and Double Arthrodesis and Severe End-Stage Flatfoot Deformity.

Few options exist for the treatment of revision and severe cases of end-stage flatfoot deformity. Triple arthrodesis or medial-approach double arthrodesis have been the standard but often do not provide enough correction of the deformity. Lateral column lengthening is a powerful procedure performed either with an Evans calcaneal osteotomy or calcaneocuboid distraction arthrodesis that can be used as an adjunct in realigning the flatfoot. We performed a retrospective radiographic review and looked at 11 consecutive cases of patients who underwent hindfoot arthrodesis with a lateral column lengthening procedure. We matched these patients with 11 control patients who underwent isolated medial-approach double arthrodesis. For the patients who underwent a lateral column lengthening procedure, we found a significant improvement in calcaneal inclination angle (p = .001) and greater correction in talar declination angle, cuboid abduction angle, and talocalcaneal angle when compared with the control group. Lateral column lengthening is a useful adjunct to hindfoot arthrodesis in the correction of revision and severe end-stage flatfoot deformity.

Two-phase equation of state for lithium fluoride.

We present an equation of state for the solid and liquid phases of lithium fluoride that covers a wide range of conditions from ambient pressure and temperature to the high pressures and temperatures exhibited in shock- and ramp-compression studies. The particular solid phase we have focused on in this work is the B1 phase. We have followed an approach where the pressure and heat-capacity functions of both phases are fit to experimental data and our own quantum molecular dynamics simulations and are then integrated in a thermodynamically consistent way to obtain the corresponding free-energy functions. This approach yields a two-phase equation of state that provides better overall agreement with experimental data than other equations of state for lithium fluoride, such as SESAME 7271v3, LEOS 2240, and the model presented by Smirnov. The last of these is a three-phase equation of state that predicts a B1-B2 transition along the shock Hugoniot at a pressure of about 140 GPa. This solid-solid transition has been a topic of speculation and debate in the literature for over 50 years, culminating in the work of Smirnov, who has developed the only potentially viable equation of state that allows for this transition. We explain why the proposed B1-B2 transition at 140 GPa is not consistent with recent velocimetry data.

Outcomes of Hindfoot Arthrodesis Supplemented With Bioactive Glass and Bone Marrow Aspirate: A Retrospective Radiographic Study.

Foot and ankle surgeons continue to explore bone graft alternatives that will be comparable to the reference standard of autologous bone. The purpose of the present study was to consider the outcomes of hindfoot arthrodesis supplemented with bioactive glass in patients at risk of delayed union and nonunion. We performed a retrospective radiographic review of 29 consecutive patients (48 joints) who had undergone arthrodesis of ≥1 joint of the hindfoot (ankle, subtalar, talonavicular, calcaneocuboid). All patients included in the present study had a minimum of 1 documented risk factor for osseous nonunion (history of previous nonunion, trauma, smoking, diabetes, Charcot arthropathy, obesity, age >65 years at surgery). The patients were followed up for a minimum of 24 weeks or until radiographic healing had been achieved. We found 12 (25.0%) nonunions across all 48 joints supplemented with bioactive glass. We found 4 (16.7%) nonunions in the subtalar joint, 1 (11.1%) in the calcaneocuboid joint, and 1 (11.1%) in the talonavicular joint. We found that hindfoot arthrodesis procedures supplemented with bioactive glass resulted in an incidence of union comparable to that with autograft and other bone graft substitutes.

Outcomes of Wound Healing and Limb Loss After Transmetatarsal Amputation in the Presence of Peripheral Vascular Disease.

Transmetatarsal amputation (TMA) is the procedure of choice in treating forefoot gangrene and infection. Foot and ankle and vascular surgeons work closely together in limb salvage, but little is known about the timing of vascular intervention to achieve a healed amputation site. This study retrospectively looked at 153 patients with peripheral vascular disease who underwent TMA with a minimum of a 3-year follow-up. A total of 102 patients received vascular intervention: 79 endovascular and 23 open bypass. The primary focus of this study was to look at the timing of vascular intervention, incidence of wound healing, and incidence of limb loss. There was an overall 44% rate of limb loss. Patients who underwent open bypass did better than those who underwent endovascular intervention with a lower incidence of limb loss (87% compared with 51%), and quicker time to wound healing. The timing of vascular intervention, performed either before or after TMA, had no association with wound healing or limb loss. Similarly, the time interval between vascular intervention and TMA had no association with wound healing or limb loss. Comorbidities, including end-stage renal disease on hemodialysis, hyperlipidemia, and congestive heart failure, showed a significant association with TMA stump nonhealing and limb loss. Body mass index ≥30, end-stage renal disease on hemodialysis, and hyperlipidemia were all risk factors for limb loss.

Comparative Nonunion Rates in Triple Arthrodesis.

The contemporary literature is unclear regarding the joint that is most "at risk" to yield a nonunion in the performance of triple arthrodesis of the foot. There is also a debate regarding the best methods of joint preparation. A retrospective radiographic review was conducted of all primary triple arthrodeses performed within in a Northern California health maintenance organization between January 2007 and June 2013. Data documenting joint preparation techniques were collected, and postoperative imaging was reviewed to measure time to osseous union. Patient demographics were also collected. One hundred fifty-two patients (157 procedures) met the inclusion criteria. The overall nonunion rate for triple arthrodesis in this series was 29.9% (47/157). The nonunion rate of the talonavicular joint was 20.4% (32/157); the nonunion rate of the calcaneocuboid joint was 17.2% (27/157); and the nonunion rate of the subtalar joint was 8.9% (14/157). In conclusion, we found the most likely joint to obtain nonunion during triple arthrodesis was the talonavicular joint. Furthermore, the most efficacious joint preparation technique was a combination joint resection or curettage with fish scaling.

Comparison of Medial Malleolar Fracture Healing at 8 Weeks After Open Reduction Internal Fixation Versus Percutaneous Fixation: A Retrospective Cohort Study.

Unstable medial malleolar fractures are treated with either standard open reduction internal fixation (ORIF) or a percutaneous approach. The percutaneous approach avoids the potentially excessive soft tissue dissection associated with an open approach but can also result in inadequate anatomic reduction. No studies have compared the incidence of radiographic healing of medial malleolar fractures between an open approach and percutaneous fixation. A retrospective comparative study was performed at a single institution across multiple sites. Electronic medical records and digital radiographs were reviewed for 845 patients who had undergone either ORIF or percutaneous screw fixation (PSF) of a medial malleolar fracture. The interval to fracture healing was measured. Logistic regression analysis was used. Of the 490 included patients, 458 (93.44%) underwent standard ORIF and 32 (6.53%) underwent PSF. Patients who underwent ORIF were 5 times more likely to have a healed fracture at 8 weeks than were patients who had undergone PSF (p < .001). Compared with standard ORIF, PSF of medial malleolar fractures leads to an increased risk of an unhealed fracture at 8 weeks. This was likely due to a combination of soft tissue interposition within the fracture site and inadequate fluoroscopic reliability, leading to poor anatomic reduction and inaccurate fixation.

Arthroscopic Medial Approach for Modified Double Arthrodesis of the Foot.

The single medial incision subtalar joint and talonavicular joint arthrodesis has been shown to be a useful alternative for the correction of hindfoot valgus deformity. We describe an arthroscopic method of joint preparation using this approach. The present case report included 6 consecutive patients aged 35 to 72 (mean ± standard deviation 55.8 ± 15.54) years (4 males [66.7%] and 2 females [33.3%]), who had undergone the medial approach for modified double arthrodesis of the foot. Of the 6 patients, 3 (50.0%) had undergone arthroscopic joint preparation and 3 (50.0%) traditional (manual) joint preparation. Osteobiologic agents were used in all patients. We found a shorter tourniquet time for the patients who had undergone an arthroscopic approach, with a mean of 110 ± 7.21 minutes, compared with a traditional joint preparation, with a mean of 121.3 ± 8.08 minutes. We also found a shorter time to radiographic union in the patients who had undergone an arthroscopic approach, all of whom showed signs of union at 6 weeks. Only 2 of the 3 patients in the traditional joint preparation group had achieved union at a mean of 10 ± 2.83 weeks, with 1 case resulting in nonunion. This technique could be a viable alternative to traditional methods of joint preparation by decreasing the operative time and improving the union rates.

Maggot debridement therapy: a systematic review.

Maggot debridement therapy is used extensively in the UK in both community and hospital situations, but remains a potentially under-used modality in many wound care markets. It promotes wound healing by performing three key processes: debridement, disinfection and growth-promoting activity. It can be used for the debridement of non-healing necrotic skin and soft tissue wounds, including pressure ulcers, venous stasis ulcers, neuropathic foot ulcers and non-healing traumatic of post-surgical wounds. With the increase in chronic diabetic foot wounds, maggot debridement therapy is a promising tool for health professionals dealing with difficult wounds. This article presents an overview of the research evidence surrounding maggot debridement therapy that serves as a guide to health professionals who may be users of this form of treatment now and in the future.

Discovery of novel selective HER-2 sheddase inhibitors through optimization of P1 moiety.

A novel series of carbamates was discovered as potent and selective HER-2 sheddase inhibitors. Significant enhancement in potency and selectivity was achieved through attenuating the P1 moiety, which was conventionally believed to be exposed to solvent.

Compelling P1 substituent affect on metalloprotease binding profile enables the design of a novel cyclohexyl core scaffold with excellent MMP selectivity and HER-2 sheddase inhibition.

A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.

Design and identification of selective HER-2 sheddase inhibitors via P1' manipulation and unconventional P2' perturbations to induce a molecular metamorphosis.

In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.

Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer.

The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.

Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells.

Overexpression and activating mutations of ErbB family members have been implicated in the development and progression of a variety of tumor types. Cleavage of the HER2 receptor by an as yet unidentified ectodomain sheddase has been shown to liberate the HER2 extracellular domain (ECD) leaving a fragment with constitutive kinase activity that can provide ligand-independent growth and survival signals to the cell. This process is clinically relevant since HER2 ECD serum levels in metastatic breast cancer patients are associated with a poorer prognosis. Thus, inhibition of the HER2 sheddase may provide a novel therapeutic approach for breast cancer. We describe the use of transcriptional profiling, pharmacological and in vitro approaches to identify the major source of HER2 sheddase activity. Real-time PCR was used to identify those ADAM family members which were expressed in HER2 shedding cell lines. siRNAs that selectively inhibited ADAM10 expression reduced HER2 shedding. In addition, we profiled over 1000 small molecules for in vitro inhibition of a panel of ADAM and MMP proteins; a positive correlation was observed only between ADAM10 inhibition and reduction of HER2 ECD shedding in a cell based assay. Finally, in vitro studies demonstrate that in combination with low doses of Herceptin, selective ADAM10 inhibitors decrease proliferation in HER2 overexpressing cell lines while inhibitors, that do not inhibit ADAM10, have no impact. These results are consistent with ADAM10 being a major determinant of HER2 shedding, the inhibition of which, may provide a novel therapeutic approach for treating a variety of cancers with active HER2 signaling.

Experimental arthritis in rats induces biomarkers of periodontitis which are ameliorated by gene therapy with tissue inhibitor of matrix metalloproteinases.

BACKGROUND: Periodontal disease (PD) and rheumatoid arthritis (RA) share many common pathophysiologic features, but a clinical relationship between the two conditions remains controversial, in part because of the confounding effects of anti-inflammatory drug therapy universally used in the latter disease. To further explore this issue, inflammatory arthritis was induced in rats to determine the effect on gingival biomarkers of inflammation and tissue destruction and to investigate the effect of a therapeutic intervention devoid of conventional anti-inflammatory properties. METHODS: Adjuvant arthritis (AA) was induced in Lewis male rats by injecting mycobacterium cell wall in complete Freund's adjuvant using standard techniques. One group of animals was treated by induction of systemic tissue inhibitor of matrix metalloproteinases (TIMP-4). At 3 weeks, arthritis severity was recorded and both paw and gingival tissues were collected for matrix metalloproteinase activity (MMP) and cytokine analysis. In addition, the maxillary jaws were removed for assessment of periodontal bone loss. RESULTS: The development of arthritis was associated with elevated joint tissue MMPs, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta levels compared to control rats. In the gingival tissue of the untreated arthritic rats, gelatinase, collagenase, TNF-alpha, and IL-1beta were also elevated compared to control rats. Periodontal bone loss and tooth mobility were also increased significantly (P <0.05) in untreated arthritic rats. All parameters improved after TIMP-4 gene therapy. CONCLUSIONS: To our knowledge, this is the first study to report an association between experimental systemic arthritis in rats and elevated gingival tissue MMPs, cytokine levels, and periodontal disease. Reversal of these changes with TIMP-4 gene therapy strengthens the pathophysiologic correlation between systemic and local disease.