Innovative, combinatorial and high-throughput approaches to degrader synthesis.

Targeted protein degraders such as PROTACs and molecular glues are a rapidly emerging therapeutic modality within industry and academia. Degraders possess unique mechanisms of action that lead to the removal of specific proteins by co-opting the cell's natural degradation mechanisms via induced proximity. Their optimisation thus far has often been largely empirical, requiring the synthesis and screening of a large number of analogues. In addition, the synthesis and development of degraders is often challenging, leading to lengthy optimisation campaigns to deliver candidate-quality compounds. This review highlights how the synthesis of degraders has evolved in recent years, in particular focusing on means of applying high-throughput chemistry and screening approaches to expedite these timelines, which we anticipate to be valuable in shaping the future of degrader optimisation campaigns.

Epidemiological Characteristics of Foot and Ankle Injuries in 2 Professional Ballet Companies: A 3-Season Cohort Study of 588 Medical Attention Injuries and 255 Time-Loss Injuries.

Background: The foot and ankle are often reported as the most common sites of injury in professional ballet dancers; however, epidemiological research focusing on foot and ankle injuries in isolation and investigating specific diagnoses is limited. Purpose: To investigate the incidence rate, severity, burden, and mechanisms of foot and ankle injuries that (1) required visiting a medical team (medical attention foot and ankle injuries; MA-FAIs) and (2) prevented a dancer from fully participating in all dance-related activities for at least 24 hours after the injury (time-loss foot and ankle injuries; TL-FAIs) in 2 professional ballet companies. Study Design: Descriptive epidemiological study. Methods: Foot and ankle injury data across 3 seasons (2016-2017 to 2018-2019) were extracted from the medical databases of 2 professional ballet companies. Injury-incidence rate (per dancer-season), severity, and burden were calculated and reported with reference to the mechanism of injury. Results: A total of 588 MA-FAIs and 255 TL-FAIs were observed across 455 dancer-seasons. The incidence rates of MA-FAIs and TL-FAIs were significantly higher in women (1.20 MA-FAIs and 0.55 TL-FAIs per dancer-season) than in men (0.83 MA-FAIs and 0.35 TL-FAIs per dancer-season) (MA-FAIs, P = .002; TL-FAIs, P = .008). The highest incidence rates for any specific injury pathology were ankle impingement syndrome and synovitis for MA-FAIs (women 0.27 and men 0.25 MA-FAIs per dancer-season) and ankle sprain for TL-FAIs (women 0.15 and men 0.08 TL-FAIs per dancer-season). Pointe work and jumping actions in women and jumping actions in men were the most common mechanisms of injury. The primary mechanism of injury of ankle sprains was jumping activities, but the primary mechanisms of ankle synovitis and impingement in women were related to dancing en pointe. Conclusion: The results of this study highlight the importance of further investigation of injury prevention strategies targeting pointe work and jumping actions in ballet dancers. Further research for injury prevention and rehabilitation strategies targeting posterior ankle impingement syndromes and ankle sprains are warranted.

Paediatric ankle cartilage lesions: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.

BACKGROUND: The evidence supporting best practice guidelines in the field of cartilage repair of the ankle are based on both low quality and low levels of evidence. Therefore, an international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to report the consensus statements on "Pediatric Ankle Cartilage Lesions" developed at the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. METHODS: Forty-three international experts in cartilage repair of the ankle representing 20 countries convened to participate in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within four working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed upon in unanimous fashion within the working groups. A final vote was then held, and the strength of consensus was characterised as follows: consensus: 51-74%; strong consensus: 75-99%; unanimous: 100%. RESULTS: A total of 12 statements on paediatric ankle cartilage lesions reached consensus during the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. Five achieved unanimous support, and seven reached strong consensus (>75% agreement). All statements reached at least 84% agreement. CONCLUSIONS: This international consensus derived from leaders in the field will assist clinicians with the management of paediatric ankle cartilage lesions.

Incidence of (Osteo)Chondral Lesions of the Ankle in Isolated Syndesmotic Injuries: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine and compare the incidence rate of (osteo)chondral lesions of the ankle in patients with acute and chronic isolated syndesmotic injuries. DESIGN: A literature search was conducted in the PubMed (MEDLINE) and EMBASE (Ovid) databases from 2000 to September 2021. Two authors independently screened the search results, and risk of bias was assessed using the MINORS (Methodological Index for Non-Randomized Studies) criteria. Studies on acute and chronic isolated syndesmotic injuries with pre-operative or intra-operative imaging were included. The primary outcome was the incidence rate with corresponding 95% confidence intervals (CIs) of (osteo)chondral lesions of the ankle in combined and separate groups of acute and chronic syndesmotic injuries. Secondary outcomes were anatomic distribution and mean size of the (osteo)chondral lesions. RESULTS: Nine articles (402 syndesmotic injuries) were included in the final analysis. Overall (osteo)chondral lesion incidence was 20.7% (95% CI: 13.7%-29.9%). This rate was 22.0% (95% CI: 17.1-27.7) and 24.1% (95% CI: 15.6-35.2) for acute and chronic syndesmotic injuries, respectively. In the combined acute and chronic syndesmotic injury group, 95.4% of the lesions were located on the talar dome and 4.5% of the lesions were located on the distal tibia. (Osteo)chondral lesion size was not reported in any of the studies. CONCLUSIONS: This meta-analysis shows that (osteo)chondral lesions of the ankle are present in 21% of the patients with isolated syndesmotic injuries. No difference in incidence rate was found between the different syndesmotic injury types and it can be concluded that the majority of lesions are located on the talar dome. PROSPERO REGISTRATION NUMBER: CRD42020176641.

Terminology for osteochondral lesions of the ankle: proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.

BACKGROUND: The evidence supporting best practice guidelines in the field of cartilage repair of the ankle is based on both low quality and low levels of evidence. Therefore, an international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to report the consensus statements on "terminology for osteochondral lesions of the ankle" developed at the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. METHODS: Forty-three international experts in cartilage repair of the ankle representing 20 countries were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within four working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed, and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed on in unanimous fashion within the working groups. A final vote was then held, and the strength of consensus was characterised as follows: consensus, 51%-74%; strong consensus, 75%-99%; unanimous, 100%. RESULTS: A total of 11 statements on terminology and classification reached consensus during the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. Definitions are provided for osseous, chondral and osteochondral lesions, as well as bone marrow stimulation and injury chronicity, among others. An osteochondral lesion of the talus can be abbreviated as OLT. CONCLUSIONS: This international consensus derived from leaders in the field will assist clinicians with the appropriate terminology for osteochondral lesions of the ankle.

SARS-CoV-2 viability on sports equipment is limited, and dependent on material composition.

The control of the COVID-19 pandemic in the UK has necessitated restrictions on amateur and professional sports due to the perceived infection risk to competitors, via direct person to person transmission, or possibly via the surfaces of sports equipment. The sharing of sports equipment such as tennis balls was therefore banned by some sport's governing bodies. We sought to investigate the potential of sporting equipment as transmission vectors of SARS-CoV-2. Ten different types of sporting equipment, including balls from common sports, were inoculated with 40 µl droplets containing clinically relevant concentrations of live SARS-CoV-2 virus. Materials were then swabbed at time points relevant to sports (1, 5, 15, 30, 90 min). The amount of live SARS-CoV-2 recovered at each time point was enumerated using viral plaque assays, and viral decay and half-life was estimated through fitting linear models to log transformed data from each material. At one minute, SARS-CoV-2 virus was recovered in only seven of the ten types of equipment with the low dose inoculum, one at five minutes and none at 15 min. Retrievable virus dropped significantly for all materials tested using the high dose inoculum with mean recovery of virus falling to 0.74% at 1 min, 0.39% at 15 min and 0.003% at 90 min. Viral recovery, predicted decay, and half-life varied between materials with porous surfaces limiting virus transmission. This study shows that there is an exponential reduction in SARS-CoV-2 recoverable from a range of sports equipment after a short time period, and virus is less transferrable from materials such as a tennis ball, red cricket ball and cricket glove. Given this rapid loss of viral load and the fact that transmission requires a significant inoculum to be transferred from equipment to the mucous membranes of another individual it seems unlikely that sports equipment is a major cause for transmission of SARS-CoV-2. These findings have important policy implications in the context of the pandemic and may promote other infection control measures in sports to reduce the risk of SARS-CoV-2 transmission and urge sports equipment manufacturers to identify surfaces that may or may not be likely to retain transferable virus.

Osteochondral Lesions of the Tibial Plafond and Ankle Instability With Ankle Cartilage Lesions: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.

BACKGROUND: An international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to present the consensus statements on osteochondral lesions of the tibial plafond (OLTP) and on ankle instability with ankle cartilage lesions developed at the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. METHODS: Forty-three experts in cartilage repair of the ankle were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within 4 working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed on in unanimous fashion within the working groups. A final vote was then held. RESULTS: A total of 11 statements on OLTP reached consensus. Four achieved unanimous support and 7 reached strong consensus (greater than 75% agreement). A total of 8 statements on ankle instability with ankle cartilage lesions reached consensus during the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. One achieved unanimous support, and seven reached strong consensus (greater than 75% agreement). CONCLUSION: These consensus statements may assist clinicians in the management of these difficult clinical pathologies. LEVEL OF EVIDENCE: Level V, mechanism-based reasoning.

Systematic review of tendon transfers in the foot and ankle using interference screw fixation: Outcomes and safety of early versus standard postoperative rehabilitation.

AIMS: To compare the outcomes of early and standard rehabilitation protocols following tendon transfers in the foot and ankle using interference screw fixation (ISF). METHODS: A systematic review was performed for relevant articles (1998 to 2020) reporting foot tendon transfer using ISF in adults. The primary outcome was early tendon failure. Secondary outcomes included function and complications. RESULTS: In total, 21 studies met the inclusion criteria, totalling 494 patients. Seven studies reported early rehabilitation protocols. The rate of early tendon failure was zero for each protocol and studies consistently reported a significant improvement in function. No differences were found comparing different rehabilitation protocols for tendon transfer for Achilles tendon pathology and foot drop. CONCLUSION: Both early and standard rehabilitation protocols are associated with high patient satisfaction and low complication rates, but currently there is a lack of evidence to support early loaded activities or motion. LEVEL OF EVIDENCE: IV Systematic review including case series.

Limited Evidence for Biological Adjuvants in Hindfoot Arthrodesis: A Systematic Review and Meta-Analysis of Clinical Comparative Studies.

BACKGROUND: The purpose of the present study was to evaluate the efficacy of biological adjuvants in patients managed with hindfoot arthrodesis. METHODS: A systematic review of the PubMed and Embase databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with use of specific search terms and eligibility criteria. Assessment of evidence was threefold: level of evidence by criteria as described in The Journal of Bone & Joint Surgery, quality of evidence according to the Newcastle-Ottawa scale, and conflicts of interest. Meta-analysis was performed with fixed-effects models for studies of low heterogeneity (I2 < 25%) and with random-effects models for studies of moderate to high heterogeneity (I2 ≥ 25%). RESULTS: A total of 1,579 hindfeet were recruited across all studies, and 1,527 hindfeet were recorded as having completed treatment and follow-up visits. The duration of follow-up ranged from 2.8 to 43 months. Twelve of the 17 included studies comprised patients with comorbidities associated with reduced healing capacity. Based on the random-effects model for nonunion rates for autograft versus allograft, the risk ratio was 0.82 (95% CI, 0.13 to 5.21; I2 = 56%; p = 0.83) in favor of lower nonunion rates for autograft. Based on the random-effects model for rhPDGF/ß-TCP versus autograft, the risk ratio was 0.90 (95% CI, 0.74 to 1.10; I2 = 59%; p = 0.30) in favor of lower nonunion rates for rhPDGF/ß-TCP. CONCLUSIONS: There is a lack of data to support the meaningful use of biological adjuvants as compared with autograft/allograft for hindfoot arthrodesis. The meta-analysis favored the use of autograft when compared with allograft but favored rhPDGF/ß-TCP when compared with autograft in the short term. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Treatment of Acute Achilles Tendon Ruptures: A Systematic Review and Meta-analysis of Complication Rates With Best- and Worst-Case Analyses for Rerupture Rates.

BACKGROUND: An acute Achilles tendon rupture (AATR) is a common injury. The controversy that has surrounded the optimal treatment options for AATRs warrants an updated meta-analysis that is comprehensive, accounts for loss to follow-up, and utilizes the now greater number of available studies for data pooling. PURPOSE: To meta-analyze the rates of all complications after the treatment of AATRs with a "best-case scenario" and "worst-case scenario" analysis for rerupture rates that assumes that all patients lost to follow-up did not or did experience a rerupture, respectively. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 1. METHODS: Two authors performed a systematic review of the PubMed and Embase databases according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines on February 17, 2020. The included studies were assessed in terms of the level of evidence, quality of evidence, and quality of the literature. A meta-analysis by fixed-effects models was performed if heterogeneity was low (I2 < 25%) and by random-effects models if heterogeneity was moderate to high (I2≥ 25%). RESULTS: Surgical treatment was significantly favored over nonsurgical treatment for reruptures. Nonsurgical treatment was significantly favored over surgical treatment for complications other than reruptures, notably infections. Minimally invasive surgery was significantly favored over open repair for complications other than reruptures (no difference for reruptures), in particular for minor complications. CONCLUSION: This meta-analysis demonstrated that surgical treatment was superior to nonsurgical treatment in terms of reruptures. However, the number needed to treat analysis produced nonmeaningful values for all treatment options, except for surgical versus nonsurgical treatment and minimally invasive surgery versus open repair. No single treatment option was revealed to be profoundly favorable with respect to every complication. The results of this meta-analysis can guide clinicians and patients in their treatment decisions that should be made jointly and on a case-by-case basis.

A Validated, Automated, 3-Dimensional Method to Reliably Measure Tibial Torsion.

BACKGROUND: Tibial torsion is a twist in the tibia measured as an angle between a proximal axis line and a distal axis line. Abnormal torsion has been associated with a variety of painful clinical syndromes of the lower limb. Measurements of normal tibial torsion reported by different authors vary by 100% (ranging from 20° to 42°), making it impossible to determine normal and pathological levels. PURPOSE: To address the problem of unreliable measurements, this study was conducted to define an automated, validated computer method to calculate tibial torsion. Reliability was compared with current clinical methods. The difference between measurements of torsion generated from computed tomography (CT) and magnetic resonance imaging (MRI) scans of the same bone, and between males and females, was assessed. STUDY DESIGN: Controlled laboratory study. METHODS: Previous methods of analyzing tibial torsion were reviewed, and limitations were identified. An automated measurement method to address these limitations was defined. A total of 56 cadaveric and patient tibiae (mean ± SD age, 37 ± 15 years; range, 17-71 years; 28 female) underwent CT scanning, and 3 blinded assessors made torsion measurements by applying 2 current clinical methods and the automated method defined in the present article. Intraclass correlation coefficient (ICC) values were calculated. Further, 12 cadaveric tibiae were scanned by MRI, stripped of tissue, and measured using a structured light (SL) scanner. Differences between torsion values obtained from CT, SL, and MRI scans, and between males and females, were compared using t tests. SPSS was used for all statistical analysis. RESULTS: When the automated method was used, the tibiae had a mean external torsion of 29°± 11° (range, 9°-65). Automated torsion assessment had excellent reliability (ICC, 1), whereas current methods had good reliability (ICC, 0.78-0.81). No significant difference was found between the torsion values calculated from SL and CT (P = .802), SL and MRI (P = .708), or MRI and CT scans (P = .826). CONCLUSION: The use of software to automatically perform measurements ensures consistency, time efficiency, validity, and accuracy not possible with manual measurements, which are dependent on assessor experience. CLINICAL RELEVANCE: We recommend that this method be adopted in clinical practice to establish databases of normal and pathological tibial torsion reference values and ultimately guide management of related conditions.

SARS-CoV-2 Transmission Risk from sports Equipment (STRIKE)

OBJECTIVESTo investigate the potential of shared sporting equipment as transmission vectors of SARS-CoV-2 during the reintroduction of sports such as soccer, rugby, cricket, tennis, golf and gymnastics. SETTINGLaboratory based live SARS-CoV-2 virus study INTERVENTIONSTen different types of sporting equipment were inoculated with 40l droplets containing clinically relevant high and low concentrations of live SARS-CoV-2 virus. Materials were then swabbed at time points relevant to sports (1, 5, 15, 30, 90 minutes). The amount of live SARS-CoV-2 recovered at each time point was enumerated using viral plaque assays, and viral decay and half-life was estimated through fitting linear models to log transformed data from each material. MAIN OUTCOME MEASUREThe primary outcome measure was quantification of retrievable SARS-CoV-2 virus from each piece of equipment at pre-determined time points. RESULTSAt one minute, SARS-CoV-2 virus was recovered in only seven of the ten types of equipment with the low dose inoculum, one at five minutes and none at 15 minutes. Retrievable virus dropped significantly for all materials tested using the high dose inoculum with mean recovery of virus falling to 0.74% at 1 minute, 0.39% at 15 minutes and 0.003% at 90 minutes. Viral recovery, predicted decay, and half-life varied between materials with porous surfaces limiting virus transmission. CONCLUSIONSThis study shows that there is an exponential reduction in SARS-CoV-2 recoverable from a range of sports equipment after a short time period, and virus is less transferrable from materials such as a tennis ball, red cricket ball and cricket glove. Given this rapid loss of viral load and the fact that transmission requires a significant inoculum to be transferred from equipment to the mucous membranes of another individual it seems unlikely that sports equipment is a major cause for transmission of SARS-CoV-2. These findings have important policy implications in the context of the pandemic and may promote other infection control measures in sports to reduce the risk of SARS-CoV-2 transmission and urge sports equipment manufacturers to identify surfaces that may or may not be likely to retain transferable virus. O_TEXTBOXWHAT IS ALREADY KNOWN ON THIS TOPICO_LITransmission of SARS-CoV-2 between individuals playing sport may be via respiratory droplets when in close proximity to an infected person. C_LIO_LISARS-CoV-2 remains viable on a variety of surfaces resulting in recommendations to reduce the sharing of sports equipment such as tennis balls when sports were re-opened. C_LI WHAT THIS STUDY ADDSO_LIThe recoverable SARS-CoV-2 viral load reduces exponentially with mean viral load of all materials less than 1% of the original inoculum after 1 minute. C_LIO_LIThe type of material has a significant effect on SARS-CoV-2 transfer, with less virus transferred from porous materials such as bovine leather or nylon woven cloth. C_LIO_LIPolicies on infection control measures in sport may be better directed towards areas other than reducing the sharing of sports equipment. C_LIO_LISports equipment manufacturers may consider using materials that absorb or retain virus as a way of reducing viral transmission from sports equipment. C_LI C_TEXTBOX

What should be done to support the mental health of healthcare staff treating COVID-19 patients?

There is an urgent need to provide evidence-based well-being and mental health support for front-line clinical staff managing the COVID-19 pandemic who are at risk of moral injury and mental illness. We describe the evidence base for a tiered model of care, and practical steps on its implementation.

Flexor digitorum longus tendon transfer to the navicular: tendon-to-tendon repair is stronger compared with interference screw fixation.

PURPOSE: To assess whether early rehabilitation could be safe after flexor digitorum longus (FDL) tendon transfer, the current biomechanical study aimed to measure tendon displacement under cyclic loading and load to failure, comparing a traditional tendon-to-tendon (TT) repair with interference screw fixation (ISF). METHODS: 24 fresh-frozen cadaveric below knee specimens underwent FDL tendon transfer. In 12 specimens a TT repair was performed via a navicular bone tunnel. In a further 12 specimens ISF was performed. Using a materials testing machine, the FDL tendon was cycled 1000 times to 150 N and tendon displacement at the insertion site measured. A final load to failure test was then performed. Statistical analysis was performed using two-way ANOVA and an independent t test, with a significance level of p < 0.05. RESULT: No significant difference in tendon displacement occurred after cyclic loading, with mean tendon displacements of 1.9 ± 1.2 mm (mean ± SD) in the TT group and 1.8 ± 1.5 mm in the ISF group (n.s.). Two early failures occurred in the ISF group, none in the TT group. Mean load to failure was significantly greater following TT repair (459 ± 96 N), compared with ISF (327 ± 76 N), p = 0.002. CONCLUSION: Minimal tendon displacement of less than 2 mm occurred during cyclic testing in both groups. The two premature failures and significantly reduced load to failure observed in the ISF group, however, indicate that the traditional TT technique is more robust. Regarding clinical relevance, this study suggests that early active range of motion and protected weight bearing may be safe following FDL tendon transfer for stage 2 tibialis posterior tendon dysfunction.

Autologous Osteochondral Transplantation for Large Osteochondral Lesions of the Talus Is a Viable Option in an Athletic Population.

BACKGROUND: Autologous osteochondral transplantation (AOT) has been shown to be a viable treatment option for large osteochondral lesions of the talus. However, there are limited data regarding the management of large lesions in an athletic population, notably with regard to return to sport. Our investigation focused on assessing both qualitative and quantitative outcomes in the high-demand athlete with large (>150 mm2) lesions. HYPOTHESIS: AOT is a viable option in athletes with large osteochondral lesions and can allow them to return to sport at their preinjury level. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The study population was limited to professional and amateur athletes (Tegner score, >6) with a talar osteochondral lesion size of 150 mm2 or greater. The surgical intervention was AOT with a donor site from the lateral femoral condyle. Clinical outcomes at a minimum of 24 months included return to sport, visual analog scale (VAS) for pain score, and Foot and Ankle Outcome Score (FAOS). In addition, graft incorporation was evaluated by magnetic resonance imaging (MRI) using MOCART (magnetic resonance observation of cartilage repair tissue) scores at 12 months after surgery. RESULTS: A total of 38 athletes, including 11 professional athletes, were assessed. The mean follow-up was 45 months. The mean lesion size was 249 mm2. Thirty-three patients returned to sport at their previous level, 4 returned at a lower level compared with preinjury, and 1 did not return to sport (mean return to play, 8.2 months). The VAS improved from 4.53 preoperatively to 0.63 postoperatively (P = .002). FAOSs improved significantly in all domains (P < .001). Two patients developed knee donor site pain, and both had 3 osteochondral plugs harvested. Univariant analysis demonstrated no association between preoperative patient or lesion characteristics and ability to return to sport. However, there was a strong correlation between MOCART scores and ability to return to sport. The area under receiver operating characteristic of the MOCART score and return to play was 0.891 (P = .005), with a MOCART score of 52.50 representing a sensitivity of 0.85 and specificity of 0.80 in determining ability to return to one's previous level of activity. CONCLUSION: Our study suggests that AOT is a viable option in the management of large osteochondral talar defects in an athletic population, with favorable return to sport level, patient satisfaction, and FAOS/VAS scores. The ability to return to sport is predicated upon good graft incorporation, and further research is required to optimize this technique. Our data also suggest that patients should be aware of the increased risk of developing knee donor site pain when 3 osteochondral plugs are harvested.

Profile of a Highly Selective Quaternized Pyrrolidine Betaine αvß6 Integrin Inhibitor-(3S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((1S and 1R,3R)-1-methyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-ium-1-yl)butanoate Synthesized by Stereoselective Methylation.

A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αvß6 integrin receptor over the other αv integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into αvß6 are described along with related analogues.

Diagnosis: History, Physical Examination, Imaging, and Arthroscopy: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.

BACKGROUND: The evidence supporting best practice guidelines in the field of cartilage repair of the ankle are based on both low quality and low levels of evidence. Therefore, an international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to report the consensus statements on "Diagnosis: History, Physical Examination, Imaging, and Arthroscopy" developed at the 2017 International Consensus Meeting on Cartilage Repair of the Ankle. METHODS: Seventy-five international experts in cartilage repair of the ankle representing 25 countries and 1 territory were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within 11 working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed upon in unanimous fashion within the working groups. A final vote was then held, and the strength of consensus was characterized as follows: consensus: 51 - 74%; strong consensus: 75 - 99%; unanimous: 100%. RESULTS: A total of 12 statements on the diagnosis of cartilage injuries of the ankle reached consensus during the 2017 International Consensus Meeting on Cartilage Repair of the Ankle. Two achieved unanimous support and 10 reached strong consensus (greater than 75% agreement). All statements reached at least 86% agreement. CONCLUSIONS: This international consensus derived from leaders in the field will assist clinicians in the diagnosis of cartilage injuries of the ankle.

Strength of Interference Screw Fixation to Cuboid vs Pulvertaft Weave to Peroneus Brevis for Tibialis Posterior Tendon Transfer for Foot Drop.

BACKGROUND: Tibialis posterior (TP) tendon transfer is an effective treatment for foot drop. Currently, standard practice is to immobilize the ankle in a cast for 6 weeks nonweightbearing, risking postoperative stiffness. To assess whether early active dorsiflexion and protected weightbearing could be safe, the current study assessed tendon displacement under cyclic loading and load to failure, comparing the Pulvertaft weave (PW) to interference screw fixation (ISF) in a cadaveric foot model. METHODS: Twenty-four cadaveric ankles had TP tendon transfer performed, 12 with the PW technique and 12 with ISF to the cuboid. The TP tendon was cycled 1000 times at 50 to 150 N and then loaded to failure in a materials testing machine. Tendon displacement at the insertion site was recorded every 100 cycles. An independent t test and 2-way analysis of variance were performed to compare techniques, with a significance level of P < .05. RESULTS: Mean tendon displacement was similar in the PW group (2.9 ± 2.5 mm [mean ± SD]) compared with the ISF group (2.4 ± 1.1 mm), P = .35. One specimen in the ISF group failed early by tendon pullout. None of the PW group failed early, although displacement of 8.9 mm was observed in 1 specimen. Mean load to failure was 419.1 ± 82.6 N in the PW group in comparison to 499.4 ± 109.6 N in the ISF group, P = .06. CONCLUSION: For TP tendon transfer, ISF and PW techniques were comparable, with no differences in tendon displacement after cyclical loading or load to failure. Greater variability was observed in the PW group, suggesting it may be a less reliable technique. CLINICAL RELEVANCE: The results indicate that early active dorsiflexion and protected weightbearing may be safe for clinical evaluation, with potential benefits for the patient compared with cast immobilization.

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Differential Motion and Compression Between the Plantaris and Achilles Tendons: A Contributing Factor to Midportion Achilles Tendinopathy?

BACKGROUND: The plantaris tendon (PT) has been thought to contribute to symptoms in a proportion of patients with Achilles midportion tendinopathy, with symptoms improving after PT excision. HYPOTHESIS: There is compression and differential movement between the PT and Achilles tendon (AT) during ankle plantarflexion and dorsiflexion. STUDY DESIGN: Descriptive laboratory study. METHODS: Eighteen fresh-frozen cadaveric ankles (mean ± SD age: 35 ± 7 years, range = 27-48 years; men, n = 9) were mounted in a customized testing rig, where the tibia was fixed but the forefoot could be moved freely. A Steinmann pin was drilled through the calcaneus, enabling a valgus torque to be applied. The soleus, gastrocnemius, and plantaris muscles were loaded with 63 N with a weighted pulley system. The test area was 40 to 80 mm above the os calcis, corresponding to where the injury is observed clinically. Medially, the AT and PT were exposed, and a calibrated flexible pressure sensor was inserted between the tendons. Pressure readings were recorded with the ankle in full dorsiflexion, full plantarflexion, and plantargrade and repeated in these positions with a 5 N·m torque, simulating increased hindfoot valgus. The pressure sensor was removed and the PT and AT marked with ink at the same level, with the foot held in neutral rotation and plantargrade. Videos and photographs were taken to assess differential motion between the tendons. After testing, specimens were dissected to identify the PT insertion. One-way analysis of variance and paired t tests were performed to make comparisons. RESULTS: The PT tendons with an insertion separate from the AT demonstrated greater differential motion through range (14 ± 4 mm) when compared with those directly adherent to the AT (2 ± 2 mm) ( P < .001). Mean pressure between the PT and AT rose in terminal plantarflexion for all specimens ( P < .001) and was more pronounced with hindfoot valgus ( P < .001). CONCLUSION: The PT inserting directly into the calcaneus resulted in significantly greater differential motion as compared with the AT. Tendon compression was elevated in terminal plantarflexion, suggesting that adapting rehabilitation tendon-loading programs to avoid this position may be beneficial. CLINICAL RELEVANCE: The insertion pattern of the PT may be a factor in plantaris-related midportion Achilles tendinopathy. Terminal range plantarflexion and hindfoot valgus both increased AT and PT compression, suggesting that these should be avoided in this patient population.