Provision of revision knee arthroplasty services across Scotland: A national audit.

BACKGROUND: There is increasing evidence that both low surgeon and centre case volumes are associated with poorer outcomes following Revision Knee Arthroplasty (rTKA). Given the unique challenges faced in Scotland relating to funding and geography, understanding details on the complexity of cases is required to guide development of future rTKA services. METHODS: Utilising the Scottish Collaborative Orthopaedic Trainee Research Network (SCOTnet) a retrospective review of all Scottish 2019 rTKA cases was undertaken. Regional leads co-ordinated local data collection using individual case note review. The number of cases performed by regions, hospitals and individual surgeons were identified. Patient demographics and case complexity (Revision Knee Complexity Classification [RKCC]) were also collected. Results were compared against current standards. RESULTS: 17 units performed rTKA, delivered by 77 surgeons. A total of 506 cases were included. The mean age was 69 years (46% male). Revision for infection accounted for 147/506 (29%) cases. Extensor compromise was present in 35/506 (7%) and 11/506 (2%) required soft tissue reconstruction. According to the RKCC - 214/503 (43%) were classified as R1 (Less complex cases), 228/503 (45%) R2 (complex cases), and 61/503 (12%) R3 (most complex / salvage cases). 5/17 (29%) units met current national guidelines for case volume/year, with only 11/77 (14%) surgeons meeting recommended individual case volumes. 37/77 (48%) surgeons performed ≤ 2 cases per year. CONCLUSIONS: Most individual centre volumes could be increased by re-organising services or locations providing rTKA within a region. This should provide better access to Multidisciplinary Team (MDT) involvement. We recorded a significant number of very low volume surgeons (≤2 year) that is contradictory to current evidence-based practice.

Organic-inorganic hybrid salt and mixed ligand Cr(III) complexes containing the natural flavonoid chrysin: Synthesis, characterization, computational, and biological studies.

Organic-inorganic hybrid salt and mixed ligand Cr(III) complexes (Cr1 and Cr2) containing the natural flavonoid chrysin were synthesized. The metal complexes were characterized using UV-Vis, Fourier-transform infrared, MS, SEM-EDX, XRD, and molar conductance measurements. Based on experimental and DFT/TD-DFT calculations, octahedral geometries for the synthesized complexes were suggested. The powder XRD analysis confirms that the synthesized complexes were polycrystalline, with orthorhombic and monoclinic crystal systems having average crystallite sizes of 21.453 and 19.600 nm, percent crystallinities of 51% and 31.37%, and dislocation densities of 2.324 × 10-3 and 2.603 × 10-3 nm-2 for Cr1 and Cr2, respectively. The complexes were subjected to cytotoxicity, antibacterial, and antioxidant studies. The in vitro biological studies were supported with quantum chemical and molecular docking computational studies. Cr1 showed significant cytotoxicity to the MCF-7 cell line, with an IC50 value of 8.08 µM compared to 30.85 µM for Cr2 and 18.62 µM for cisplatin. Cr2 showed better antibacterial activity than Cr1. The higher E HOMO (-5.959 eV) and dipole moment (10.838 Debye) values of Cr2 obtained from the quantum chemical calculations support the observed in vitro antibacterial activities. The overall results indicated that Cr1 is a promising cytotoxic drug candidate.

Cytotoxicity and Antibacterial Potentials of Mixed Ligand Cu(II) and Zn(II) Complexes: A Combined Experimental and Computational Study.

[Cu(C15H9O4)(C12H8N2)O2C2H3]·3H2O (1) and [Zn(C15H9O4)(C12H8N2)]O2C2H3 (2) have been synthesized and characterized by ultraviolet-visible (UV-vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, mass spectrometry, thermogravimetric analysis/differential thermal analysis (TGA/DTA), X-ray diffraction (XRD), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDX), and molar conductance, and supported by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. Square pyramidal and tetrahedral geometries are proposed for Cu(II) and Zn(II) complexes, respectively, and the XRD patterns showed the polycrystalline nature of the complexes. Furthermore, in vitro cytotoxic activity of the complexes was evaluated against the human breast cancer cell line (MCF-7). A Cu(II) centered complex with an IC50 value of 4.09 µM was more effective than the Zn(II) centered complex and positive control, cisplatin, which displayed IC50 values of 75.78 and 18.62 µM, respectively. In addition, the newly synthesized complexes experienced the innate antioxidant nature of the metal centers for scavenging the DPPH free radical (up to 81% at 400 ppm). The biological significance of the metal complexes was inferred from the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy band gap, which was found to be 2.784 and 3.333 eV, respectively for 1 and 2, compared to the ligands, 1,10-phenathroline (4.755 eV) and chrysin (4.403 eV). Moreover, the molecular docking simulations against estrogen receptor alpha (ERα; PDB: 5GS4) were strongly associated with the in vitro biological activity results (E B and K i are -8.35 kcal/mol and 0.76 µM for 1, -7.52 kcal/mol and 3.07 µM for 2, and -6.32 kcal/mol and 23.42 µM for cisplatin). However, more research on in vivo cytotoxicity is suggested to confirm the promising cytotoxicity results.

Cytotoxic mixed-ligand complexes of Cu(II): A combined experimental and computational study.

Herein, we report the synthesis of mixed-ligand Cu(II) complexes of metformin and ciprofloxacin drugs together with 1,10-phenanthroline as a co-ligand. The synthesized complexes were characterized using different spectroscopic and spectrometric techniques. In vitro cytotoxic activity against human breast adenocarcinoma cancer cell line (MCF-7) as well as antibacterial activity against two gram-negative and two gram-positive bacterial strains were also investigated. The analyses of the experimental results were supported using quantum chemical calculations and molecular docking studies against estrogen receptor alpha (ERα; PDB: 5GS4). The cytotoxicity of the [Cu(II) (metformin) (1,10-phenanthroline)] complex (1), with IC50 of 4.29 µM, and the [Cu(II) (ciprofloxacin) (1,10-phenanthroline)] complex (2), with IC50 of 7.58 µM, were found to be more effective than the referenced drug, cisplatin which has IC50 of 18.62 µM against MCF-7 cell line. The molecular docking analysis is also in good agreement with the experimental results, with binding affinities of -7.35, -8.76 and -6.32 kcal/mol, respectively, for complexes 1, 2 and cisplatin against ERα. Moreover, complex 2 showed significant antibacterial activity against E. coli (inhibition diameter zone, IDZ, = 17.3 mm), P. aeruginosa (IDZ = 17.08 mm), and S. pyogen (IDZ = 17.33 mm), at 25 µg/ml compared to ciprofloxacin (IDZ = 20.0, 20.3, and 21.3 mm), respectively. Our BOILED-egg model indicated that the synthesized metal complexes have potentially minimal neurotoxicity than that of cisplatin.

Functional characterization of cultivable gut bacterial communities associated with rugose spiralling whitefly, Aleurodicus rugioperculatus Martin.

Gut symbiotic bacteria provide protection and nutrition to the host insect. A high reproductive rate and dispersal ability of the rugose spiralling whitefly help this polyphagous species to develop and thrive on many horticultural crops. In this study, we isolated the cultivable gut bacteria associated with rugose spiralling whitefly and demonstrated their role in the host insect. We also studied the influence of antibiotics on the rugose spiralling whitefly oviposition. A total of 70 gut bacteria were isolated from the second nymphal stage of rugose spiralling whitefly reared on coconut, banana, and sapota using seven growth media. From the 70 isolates, chitinase, siderophore (51), protease (44), and Glutathione-S-Transferase producers (16) were recorded. The activities of chitinase, siderophore, protease, and Glutathione-S-Transferase in the gut bacterial isolates of rugose spiralling whitefly ranged from 0.07 to 3.96 µmol-1 min-1 mL-1, 10.01 to 76.93%, 2.10 to 83.40%, and 5.21 to 24.48 nmol-1 min-1 mL-1 µg-1 protein, respectively. The16S rRNA gene sequence analysis revealed that bacterial genera associated with the gut of rugose spiralling whitefly included Bacillus, Exiguobacterium, Acinetobacter, Lysinibacillus, Arthrobacter, and Pseudomonas. Based on the susceptibility of the gut bacteria to antibiotics, 11antibiotic treatments were administered to the host plant leaves infested with the nymphal stages. The antibiotics were evaluated for their effect on rugose spiralling whitefly oviposition. Among the antibiotic treatments, carbenicillin (100 µg mL-1) + ciprofloxacin (5 µg mL-1) significantly reduced the oviposition (13 eggs spiral-1) and egg hatchability (61.54%) of rugose spiralling whitefly. Disruption of chitinase, siderophore, protease, and detoxification enzyme producers and elimination of these symbionts through antibiotics altered the host insect physiology and indirectly affected whitefly oviposition. In conclusion, gut bacteria-based management strategies might be used as insecticides for the effective control of whiteflies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-03081-3.

Delineating the inherent functional descriptors and biofunctionalities of pectic polysaccharides.

Pectin is a plant-based heteropolysaccharide macromolecule predominantly found in the cell wall of plants. Pectin is commercially extracted from apple pomace, citrus peels and sugar beet pulp and is widely used in the food industry as a stabilizer, emulsifier, encapsulant, and gelling agent. This review highlights various parameters considered important for describing the inherent properties and biofunctionalities of pectins in food systems. These inherent descriptors include monosaccharide composition, galacturonic acid content, degree of esterification, molecular weight, structural morphology, functional group analysis, and functional properties, such as water and oil holding capacity, emulsification, foaming capacity, foam stability, and viscosity. In this study, we also delineate their potential as a nutraceutical, prebiotic, and carrier for bioactive compounds. The biofunctionalities of pectin as an anticancer, antioxidant, lipid-lowering, and antidiabetic agent are also conceptually elaborated in the current review. The multidimensional characteristics of pectin make it a potential candidate for use in food and biomedical science.

Improved survival prediction for oropharyngeal cancer beyond TNMv8.

PURPOSE: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. MATERIAL AND METHODS: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. RESULTS: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE] ±â€¯SE = 0.72 ±â€¯0.02 vs 0.53 ±â€¯0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPE = 0.79 vs 0.79, p = 0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76 ±â€¯0.02). CONCLUSIONS: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.

Age stratified, matched comparison of unicompartmental and total knee replacement.

BACKGROUND: Unicompartmental knee replacement (UKR) tends to provide better function but has a higher revision rate than total knee replacement (TKR). The aim was to determine if this occurred in all age groups. METHODS: Two large, non-registry, prospective cohorts with median 10-year follow-up (2252 TKR, 1000 medial UKR) were identified. All UKR met recommended indications. TKR with an inappropriate disease pattern for medial UKR were excluded. Knees were propensity score-matched within age-strata (<60 years at operation, 60 to <75, 75+) and compared using Oxford Knee Score (OKS), Kaplan-Meier revision rates and a composite failure, defined as any of revision, reoperation or no improvement in OKS. RESULTS: One thousand five hundred and eighty-two TKR and UKR were matched. Results are reported TKR vs UKR for ages <60, 60 to <75 and 75+. Median 10-year OKS were 33 vs 45 (p < 0.001), 36 vs 42 (p < 0.001) and 36 vs 38 (p = 0.25). Ten-year revision rates were 11% vs 7%, 5% vs 5%, and 5% vs 10%, (none significant). The composite failures occurred 8%, 5% and 5% more frequently with TKR than UKR (none significant). CONCLUSIONS: In this matched study UKR provided better functional outcomes in all age groups, particularly the young, and provided substantially more excellent outcomes. Although in older groups TKR tended to have a lower revision rate, in the young UKR had a lower revision rate. This was surprising and was perhaps because in this study UKR was, as recommended, only used for bone-on-bone arthritis, whereas in young patients it is widely used for early arthritis, which is associated with a high failure rate. This study supports the use of UKR with recommended indications, in all age groups.

Remarkable thermal conductivity enhancement in Ag-decorated graphene nanocomposites based nanofluid by laser liquid solid interaction in ethylene glycol.

We report on the synthesis and enhanced thermal conductivity of stable Ag-decorated 2-D graphene nanocomposite in ethylene glycol based nanofluid by laser liquid solid interaction. A surfactant free nanofluid of Ag nanoparticles anchored onto the 2-D graphene sheets were synthesized using a two-step laser liquid solid interaction approach. In order to understand a pulsed Nd:YAG laser at the fundamental frequency (λ = 1,064 nm) to ablate Ag and graphite composite target submerged in ethylene glycol (EG) to form AgNPs decorated 2-D GNs-EG based nanofluid. From a heat transfer point of view, it was observed that the thermal conductivity of this stable Ag-graphene/EG is significantly enhanced by a factor of about 32.3%; this is highest reported value for a graphene based nanofluid.

Palliative Lung Radiotherapy: Higher Dose Leads to Improved Survival?

AIMS: Choosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients. MATERIALS AND METHODS: A retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated. RESULTS: Univariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), 'lifelong never' smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively. CONCLUSION: In this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status.

Biosynthesis, synthetic studies, and biological activities of the jadomycin alkaloids and related analogues.

The jadomycins are an expanding class of compounds produced from Streptomyces venezuelae, by diverting the normal biosynthesis which provides the antibiotic chloramphenicol. In the presence of amino acids, and either by heat shock, supplementation with ethanol, or when phage SV1 is added to the culture, the formation of substituted jadomycins and benzo[b]phenanthridines can be achieved. The first part of this review provides details of intermediates involved in the biosynthesis of the jadomycins and the related benzo[b]phenanthridines. Both the jadomycins and the benzo[b]phenanthridines share biosynthetic pathways with a large class of naturally occurring compounds known as the angucyclines. The biosynthetic pathways diverge when it is postulated that an intermediate quinone, such as 3-(2-formyl-6-hydroxy-4-methylphenyl)-8-hydroxy-1,4-naphthoquinone-2-carboxylic acid is formed. The quinone then undergoes reactions with amino acids and derivatives in the culture medium to ultimately afford a library of jadomycins and a few benzo[b]phenanthridines. The second part of the review initially details synthetic efforts toward the synthesis of the naturally occurring benzo[b]phenanthridine, phenanthroviridin, and then outlines methods that have been used to assemble a selection of jadomycins. Total syntheses of jadomycin A and B, derived from l-isoleucine, are described. In addition, the synthesis of the aglycon of jadomycins M, W, S, and T is outlined. These four jadomycins were derived from l-methionine, l-tryptophan, l-serine and l-threonine respectively. As a result of these synthetic efforts, the structures of jadomycin S and T have been revised. The third part of the review describes the reported antibacterial and anticancer activities of both the jadomycins and some naturally occurring benzo[b]phenanthridines.

Lifetime revision risk for medial unicompartmental knee replacement is lower than expected.

PURPOSE: Unicompartmental knee replacement (UKR) is widely considered to be a pre-total knee replacement (TKR) particularly in the young. The implication of this is that it is sensible to do a UKR, even though it will be revised at some stage, as it will delay the need for a TKR. The chance of a UKR being revised during a patient's life time has not previously been calculated. The aim of this study was to estimate this lifetime revision risks for patients of different ages undergoing UKR. METHODS: Calculations were based on data from a designer series of 1000 medial Oxford UKR with mean 10-year follow up. These UKR were implanted for the recommended indications using the recommended surgical technique. Parametric survival models were developed for patients of different ages based on observed data, and were extrapolated using a Markov model to estimate lifetime revision risk. RESULTS: The estimated lifetime revision risk reduced with increasing age at surgery. Lifetime revision risk at age 55 was 15% (95% CI 12-19), at 65 it was 11% (8-13), at 75 it was 7% (5-9), and at 85 it was 4% (3-5). CONCLUSION: Provided UKR is used appropriately, the lifetime revision risk is markedly lower than expected. UKR should be considered to be a definitive knee replacement rather than a Pre-TKR even in the young. These lifetime estimates, alongside established benefits for UKR in speed of recovery, morbidity, mortality and function, can be discussed with appropriate patients when considering whether to implant a UKR or TKR. LEVEL OF EVIDENCE: III.

Bupivacaine Extended-Release Liposomal Injection Versus Bupivacaine HCl for Early Postoperative Pain Control Following Wrist Operations: A Prospective, Randomized Control Trial.

PURPOSE: This study evaluated pain control after wrist operations using a long-acting local anesthetic, liposomal bupivacaine, compared with the standard local anesthetic, bupivacaine HCl. METHODS: Patients undergoing elective carpometacarpal joint arthroplasty and proximal row carpectomy were eligible. Those meeting inclusion criteria were enrolled before surgery and were randomized to receive an intraoperative injection of liposomal bupivacaine or bupivacaine HCl. Primary outcomes included intraoperative and postoperative opioid requirements and pain levels. On the first 4 postoperative days, phone contact assessed pain level by numeric rating scale, number of opioids taken in each 24-hour period, and efficacy of anesthesia and opioid side effects with overall benefit of analgesia score. RESULTS: Postoperative pain scores for 52 patients measured by numeric rating scale demonstrated that liposomal bupivacaine and bupivacaine HCl were similar for pain control. Pain scores and opioid use were similar during the first 4 postoperative days. Opioid use on day 1 was slightly lower with liposomal bupivacaine. There were no statistically significant differences in any postoperative outcome between groups. CONCLUSIONS: Liposomal bupivacaine and bupivacaine HCl have similar effects in the treatment of early postoperative pain after trapeziometacarpal suspension arthroplasty and proximal row carpectomy. Neither drug demonstrated a clear advantage in this study. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Mid- to long-term function and implant survival of ACL reconstruction and medial Oxford UKR.

PURPOSE: The purpose of this study was to describe mid- to long-term outcomes of anterior cruciate ligament (ACL) reconstruction with simultaneous or staged medial unicompartmental knee replacement (UKR), and compare outcomes between (1) young patients aged younger than 55 at surgery and those older, (2) those with long-term follow-up greater than 10 years, (3) cemented and cementless UKR, and (4) compare outcomes to those with an intact ACL. PATIENTS AND METHODS: We identified knees with staged or simultaneous ACL reconstruction and medial UKR from a prospectively followed designer UKR cohort, and describe mean Oxford Knee Score (OKS), mean Tegner activity score and Kaplan-Meier survival estimates. We matched these knees to ACL-intact knees. RESULTS: Seventy-six consecutive UKR with staged or simultaneous ACL reconstruction were identified with mean six-year follow-up (range 1-15). There was significant improvement in OKS and Tegner score with surgery. At most recent follow-up, OKS was 41.0 (range 11 to 48), and Tegner score 3.6 (0 to 8). There were three revisions occurring at a mean of five years post-operatively. The five-, 10- and 15-year survival estimates were 97% (95% confidence interval [CI] 93-100), 92% (83-100), and 92% (83-100). There was no difference in functional scores or implant survival in young patients, those with long-term follow-up (>10 years), those with cementless fixation, or when compared to ACL intact knees. CONCLUSION: These results demonstrate excellent mid- to long-term function and survival of selected patients who have undergone ACL reconstruction and medial UKR. Their outcome was similar to those with intact ACLs.

Validity of the CES-D for depression screening in military service members with a history of mild traumatic brain injury.

Primary Objective: To advance knowledge about the value of the Center for Epidemiologic Studies - Depression scale (CES-D) for depression screening in military service members with a history of mild traumatic brain injury (mTBI). Research Design: Retrospective data from 336 military service members with a history of mTBI were extracted from a TBI Repository at a large military medical center. Participants included in this study screened positive for mTBI in a primary care clinic or soldier readiness processing center and were enrolled in the TBI repository from November 6, 2014 to May 31, 2017. At the time of enrollment, participants completed the CES-D and their electronic medical records (EMR) were searched for diagnoses of depressive disorders. Methods and Procedures: Receiver-operating characteristic (ROC) analysis of the CES-D was used to discriminate cases with and without depression diagnoses. Main Outcomes and Results: Area under the ROC curve (AUC) was .897. Sensitivity (.824) and specificity (.826) were maximized at a cut score of 18 or greater, slightly higher than the standard cut of 16 established for civilian samples. Conclusions: Results suggest that the CES-D is a valid screening instrument for depressive disorders in military samples with a history of mTBI.

Functional Outcome and Revision Rate Are Independent of Limb Alignment Following Oxford Medial Unicompartmental Knee Replacement.

BACKGROUND: There is controversy about optimal limb alignment following knee replacement. An aim of using Oxford medial unicompartmental knee replacement (UKR) implants is to accurately restore normal ligament tension in the knee, thereby restoring normal kinematics. This return to normal tension typically results in a return to prearthritic alignment, which is frequently varus. The aim of this study was to investigate the relationship between postoperative limb alignment and postoperative patient-reported outcome and implant revision rate. METHODS: We used a consecutive cohort of 891 knees with cemented Oxford medial UKR implants with a mean 10-year follow-up and recorded alignment. We grouped knees according to postoperative mechanical alignment as marked varus (estimated at 10°), mild varus (estimated at 5°), neutral, and valgus. The mean Oxford Knee Score (OKS) was calculated at 5 and 10 years postoperatively. Revision risk was assessed by survival analysis and component-time incidence rates. RESULTS: Postoperatively, 67 (8%) of the 891 knees were in marked varus; 308 (35%), in mild varus; 508 (57%), in neutral; and 8 (1%), in valgus. The valgus group (8 knees) was too small for further analysis. The mean OKS (and standard deviation [SD]) at 10 years postoperatively was 41.7 ± 7 for marked varus, 40.5 ± 8 for mild varus, and 39.4 ± 9 for neutral alignment (p = 0.28). At 10 years, 92%, 85%, and 76% achieved a good or excellent OKS outcome, respectively (p = 0.02). Twelve-year survival rates were 93.3% for marked varus, 93.2% for mild varus, and 93.6% for neutral alignment, respectively (p = 0.53). Revision incidence rates per 100 component-years were 0.49 (95% confidence interval [CI], 0.2 to 1.5), 0.36 (95% CI, 0.2 to 0.7), and 0.54 (95% CI, 0.4 to 0.8), respectively, and were not significantly different (p = 0.53). CONCLUSIONS: Marked postoperative varus mechanical alignment of an estimated 10° was present in 8%, and mild varus of about 5° was present in 35%. Increasing varus alignment was associated with an increasing percentage of good or excellent OKS outcomes, but otherwise there were no significant differences between alignment groups in patient-reported outcome or revision rate. These data support the standard operative technique for the Oxford UKR, which aims to restore ligament tension and therefore prearthritic alignment rather than neutral mechanical alignment. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Equus caballus papillomavirus 8 (EcPV8) associated with multiple viral plaques, viral papillomas, and squamous cell carcinoma in a horse.

BACKGROUND: Equus caballus papillomavirus 8, a recently discovered virus, has been reported to cause generalised papillomavirus in horses. OBJECTIVES: To describe a case in which multiple viral plaques, viral papillomas, squamous cell carcinoma (SCC) in situ and invasive squamous cell carcinoma (ISCC) were associated with EcPV8 in a horse. STUDY DESIGN: Case report. METHODS: A 16-year-old mixed breed horse presented with dozens of raised crusted papular to nodular lesions over a course of 4 years. Masses had been surgically excised four times and cisplatin beads and emulsion were implanted on three different occasions; however new masses continue to develop in sites of previous masses as well as new sites. RESULTS: Multiple viral plaques, viral papillomas, SCC in situ and ISCC, localised to the inguinal region, were diagnosed via histopathology. EcPV8 DNA was detected via PCR. MAIN LIMITATIONS: Since only a few cases have been reported, we do not know the incidence of EcPV8 nor how often it may be associated with SCC in situ or ISCC without further study. CONCLUSIONS: This is the fourth reported case of viral papillomatosis in the context of an EcPV8 infection in a horse. This is the first case in which SCC has been associated with EcPV8.

Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.

Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.

Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2T202/Y204 protein levels at higher compound concentrations.