Pre-existing knee osteoarthritis and severe joint depression are associated with the need for total knee arthroplasty after tibial plateau fracture in patients aged over 60 years.

Aims: This study aims to determine the rate of and risk factors for total knee arthroplasty (TKA) after operative management of tibial plateau fractures (TPFs) in older adults. Methods: This is a retrospective cohort study of 182 displaced TPFs in 180 patients aged ≥ 60 years, over a 12-year period with a minimum follow-up of one year. The mean age was 70.7 years (SD 7.7; 60 to 89), and 139/180 patients (77.2%) were female. Radiological assessment consisted of fracture classification; pre-existing knee osteoarthritis (OA); reduction quality; loss of reduction; and post-traumatic OA. Fracture depression was measured on CT, and the volume of defect estimated as half an oblate spheroid. Operative management, complications, reoperations, and mortality were recorded. Results: Nearly half of the fractures were Schatzker II AO B3.1 fractures (n = 85; 47%). Radiological knee OA was present at fracture in 59/182 TPFs (32.6%). Primary management was fixation in 174 (95.6%) and acute TKA in eight (4.4%). A total of 13 patients underwent late TKA (7.5%), most often within two years. By five years, 21/182 12% (95% confidence interval (CI) 6.0 to 16.7) had required TKA. Larger volume defects of greater depth on CT (median 15.9 mm vs 9.4 mm; p < 0.001) were significantly associated with TKA requirement. CT-measured joint depression of > 12.8 mm was associated with TKA requirement (area under the curve (AUC) 0.766; p = 0.001). Severe joint depression of > 15.5 mm (hazard ratio (HR) 6.15 (95% CI 2.60 to 14.55); p < 0.001) and pre-existing knee OA (HR 2.70 (95% CI 1.14 to 6.37); p = 0.024) were independently associated with TKA requirement. Where patients with severe joint depression of > 15.5 mm were managed with fixation, 11/25 ultimately required TKA. Conclusion: Overall, 12% of patients aged ≥ 60 years underwent TKA within five years of TPF. Severe joint depression and pre-existing knee arthritis were independent risk factors for both post-traumatic OA and TKA. These features should be investigated as potential indications for acute TKA in older adults with TPFs.

Outcome Following Intramedullary Nailing of Tibial Diaphyseal Fractures: Suprapatellar Nail Insertion Results in Superior Radiographic Parameters But No Difference in Mid-Term Function.

BACKGROUND: The primary aim of this study was to compare the radiographic parameters (nail insertion-point accuracy [NIPA] and fracture malalignment) of patients who had undergone tibial intramedullary nailing via the suprapatellar (SP) and infrapatellar (IP) approaches. The secondary aims were to compare clinical outcomes and patient-reported outcomes (PROs) between these approaches. METHODS: All adult patients with an acute tibial diaphyseal fracture who underwent intramedullary nailing at a single level-I trauma center over a 4-year period (2017 to 2020) were retrospectively identified. The nailing approach (SP or IP) was at the treating surgeon's discretion. Intraoperative and immediate postoperative radiographs were reviewed to assess NIPA (mean distance from the optimal insertion point) and malalignment (≥5°). Medical records and radiographs were reviewed to evaluate the rates of malunion, nonunion, and other postoperative complications. The Oxford and Lysholm Knee Scores (OKS and LKS) and patient satisfaction (0 = completely dissatisfied, 100 = completely satisfied) were obtained via a postal survey at a minimum of 1 year postoperatively. RESULTS: The cohort consisted of 219 consecutive patients (mean age, 48 years [range, 16 to 90 years], 51% [112] male). There were 61 patients (27.9%) in the SP group and 158 (72.1%) in the IP group. The groups did not differ in baseline demographic or injury-related variables. SP nailing was associated with superior coronal NIPA (p < 0.001; 95% confidence interval [CI] for IP versus SP, 1.17 to 3.60 mm) and sagittal NIPA (p < 0.001; 95% CI, 0.23 to 0.97 mm) and with a reduced rate of malalignment (3% [2 of 61] versus 11% [18 of 158] for IP; p = 0.030). PROs were available for 118 of 211 patients (56%; 32 of 58 in the SP group and 86 of 153 in the IP group) at a mean of 3 years (range, 1.2 to 6.5 years). There was no difference between the SP and IP groups in mean OKS (36.5 versus 39.6; p = 0.246), LKS (71.2 versus 73.5; p = 0.696), or satisfaction scores (81.4 versus 79.9; p = 0.725). CONCLUSIONS: Compared with IP nailing, SP nailing of tibial shaft fractures was associated with superior NIPA and a reduced rate of intraoperative malalignment but not of malunion at healing. However, the superior NIPA may not be clinically important. Furthermore, there were no differences in PROs at mid-term follow-up. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Common peroneal nerve injury after tibial plateau fractures: A case series.

Introduction: Common peroneal nerve (CPN) injury is a rare but significant complication of knee trauma. Given its low incidence, there is limited published evidence, but reports have shown dislocations and fractures associated with varus deformity are more likely to injure the nerve, causing foot drop. This study aims to document the incidence and outcome of CPN palsy in tibial plateau fractures (TPF). Methods: We reviewed 746 cases of tibial plateau fractures treated between 2011 and 2020. We analysed patients' demographics, injury mechanisms, clinical course, and complications, and identified those with CPN palsies. Fractures were classified using the Schatzker, Luo and AO/OTA systems. The details of the CPN injury, including nerve conduction studies, duration of symptoms and outcome were recorded. Results: We identified 11 patients who had concurrent TPFs and CPN palsies, an overall incidence of 1.47 %. Most fractures involved the medial column (n = 9), with the C3 fragmentary TPF pattern being the most common (n = 4). The incidence of CPN injury was higher in medial fractures (5 %) and bicondylar fractures (3 %). We also found that most patients (n = 9) recovered full neurological function within 2 years. Discussion: This is the first study looking at a patient cohort sustaining concurrent TPFs and CPN injuries. It is a rare complication but should be looked for in high-risk medial and bicondylar fractures. We found that prognosis is better in TPF-associated CPN palsy than in other knee trauma, and that the majority of patients can expect a full recovery of nerve function.

Tibial plateau fractures in older adults are associated with a clinically significant deterioration in health-related quality of life.

To investigate health-related quality of life (HRQoL) of older adults (aged ≥ 60 years) after tibial plateau fracture (TPF) compared to preinjury and population matched values, and what aspects of treatment were most important to patients. We undertook a retrospective, case-control study of 67 patients at mean 3.5 years (SD 1.3; 1.3 to 6.1) after TPF (47 patients underwent fixation, and 20 nonoperative management). Patients completed EuroQol five-dimension three-level (EQ-5D-3L) questionnaire, Lower Limb Function Scale (LEFS), and Oxford Knee Scores (OKS) for current and recalled prefracture status. Propensity score matching for age, sex, and deprivation in a 1:5 ratio was performed using patient level data from the Health Survey for England to obtain a control group for HRQoL comparison. The primary outcome was the difference in actual (TPF cohort) and expected (matched control) EQ-5D-3L score after TPF. TPF patients had a significantly worse EQ-5D-3L utility (mean difference (MD) 0.09, 95% confidence interval (CI) 0.00 to 0.16; p < 0.001) following their injury compared to matched controls, and had a significant deterioration (MD 0.140, 95% CI 0 to 0.309; p < 0.001) relative to their preoperative status. TPF patients had significantly greater pre-fracture EQ-5D-3L scores compared to controls (p = 0.003), specifically in mobility and pain/discomfort domains. A decline in EQ-5D-3L greater than the minimal important change of 0.105 was present in 36/67 TPF patients (53.7%). Following TPF, OKS (MD -7; interquartile range (IQR) -1 to -15) and LEFS (MD -10; IQR -2 to -26) declined significantly (p < 0.001) from pre-fracture levels. Of the 12 elements of fracture care assessed, the most important to patients were getting back to their own home, having a stable knee, and returning to normal function. TPFs in older adults were associated with a clinically significant deterioration in HRQoL compared to preinjury level and age, sex, and deprivation matched controls for both undisplaced fractures managed nonoperatively and displaced or unstable fractures managed with internal fixation.

Morphometric analysis of the human common hepatic artery reveals a rich and accessible target for sympathetic liver denervation.

This study quantified the distribution of nerves and adjacent anatomies surrounding human common hepatic artery (CHA) as guidance for catheter based denervation. CHA collected from cadaveric human donors (n = 20) were histologically evaluated and periarterial dimensions and distributions of nerves, lymph nodes, pancreas and blood vessels quantified by digital morphometry. Nerve abundance decreased significantly with distance from the aortic ostium (P < 0.0001) and was higher in the Superior/Inferior compared to the Anterior/Posterior quadrants (P = 0.014). In each locational group, nerves were absent from the artery wall, and starting 0.5-1.0 mm from the lumen exhibited a first order dependence on radial distance, fully defined by the median distance. Median subject-averaged nerve distance to the lumen was 2.75 mm, ranging from 2.1-3.1 mm in different arterial segments and quadrants and 2.0-3.5 mm in individuals. Inter-individual variance was high, with certain individuals exhibiting 50th and 75th nerve distances of, respectively, 3.5 and 6.5 mm The pancreas rarely approached within 4 mm of the lumen proximally and 2.5 mm more distally. The data indicate that the CHA is a rich and accessible target for sympathetic denervation regardless of sex and diabetes, with efficacy and safety most optimally balanced proximally.

"Walking the nitrogen around the ring": Chemical synthesis and spectroscopic characterization of novel 4-, 5-, 6-, and 7-azaindazole analogs of the synthetic cannabinoid receptor agonist MDMB-PINACA.

Over the past decade, synthetic cannabinoid receptor agonists (SCRAs) have rapidly evolved to encompass a wide range of structurally diverse new psychoactive substances (NPS), including derivatives that incorporate indole, indazole, 7-azaindole, γ-carbolinone, or carbazole heterocyclic scaffolds. The introduction of legislative measures seeking to control the availability of NPS on the recreational drug scene has likely contributed to the continued emergence of novel SCRA analogs, which often evade regulatory control. However, the detection and/or identification of azaindazole-type SCRAs in seized material has not yet been reported (September, 2021). It is plausible that SCRAs bearing a 1,3-disubstituted azaindazole scaffold may possess cannabimimetic activity, given their structural similarity with known indole, indazole, and azaindole SCRAs. In view of these antecedents, a set of four novel isomeric 4-, 5-, 6-, and 7-azaindazole analogs of the known potent indazole SCRA, MDMB-PINACA, were synthesized using a Pd-catalyzed aminocarbonylation strategy. The complementary use of ultraviolet (UV) and infrared (IR) spectroscopy, gas chromatography-mass spectrometry (GC-MS), high resolution mass spectrometry (HRMS), 1D- and 2D-nuclear magnetic resonance (NMR) spectroscopy, and high performance liquid chromatography (HPLC) has permitted the spectroscopic differentiation, unambiguous structural assignment, and rapid separation of novel isomeric 4-, 5-, 6-, and 7-azaindazole analogs of the indazole SCRA, MDMB-PINACA.

Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax.

Lipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by 1H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on 1H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution.

The indazole scaffold represents a promising pharmacophore, commonly incorporated in a variety of therapeutic drugs. Although indazole-containing drugs are frequently marketed as the corresponding N-alkyl 1H- or 2H-indazole derivative, the efficient synthesis and isolation of the desired N-1 or N-2 alkylindazole regioisomer can often be challenging and adversely affect product yield. Thus, as part of a broader study focusing on the synthesis of bioactive indazole derivatives, we aimed to develop a regioselective protocol for the synthesis of N-1 alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for N-1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we observed > 99% N-1 regioselectivity for 3-carboxymethyl, 3-tert-butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on N-1/N-2 regioisomeric distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate electrophiles, while maintaining a high degree of N-1 regioselectivity.

Open Reduction and Internal Fixation for Humeral Shaft Nonunion: Bone Grafting Is Not Routinely Required and Avoids Donor Site Morbidity.

OBJECTIVES: To document union rate, complications and patient-reported outcomes after open reduction and internal fixation (ORIF), with and without bone grafting (BG), for humeral diaphyseal nonunion after failed nonoperative management. DESIGN: Retrospective. SETTING: University teaching hospital. PATIENTS AND INTERVENTION: From 2008 to 2017, 86 consecutive patients [mean age 59 years (range 17-86), 71% (n = 61/86) women] underwent nonunion ORIF (plate and screws) at a mean of 7 months postinjury (range 3-21.5). Eleven (13%) underwent supplementary BG. MAIN OUTCOME MEASUREMENTS: Union rate and complications for 83 patients (97%) at a mean of 10 months (3-61). Patient-reported outcomes (QuickDASH, EQ-5D, EQ-VAS, SF-12, satisfaction) for 53 living, cognitively-intact patients (78%) at a mean of 4.9 years (0.3-9.2). RESULTS: Ninety-three percent (n = 77/83) achieved union after nonunion ORIF. Complications included recalcitrant nonunion (7%, n = 6/83), iatrogenic radial nerve palsy (6%, n = 5/83), infection (superficial 7%, n = 6/83; deep 2%, n = 2/83), and iliac crest donor site morbidity (38%, n = 3/8). The union rate with BG was 78% (n = 7/9) and without was 95% (n = 70/74; P = 0.125), and was not associated with the nonunion type (atrophic 91%, n = 53/58; hypertrophic 96%, n = 24/25; P = 0.663). Median QuickDASH was 22.7 (0-95), EQ-5D 0.710 (-0.181-1), EQ-visual analog scale 80 (10-100), SF-12 physical component summary 41.9 (16-60.5), and mental component summary 52.6 (18.7-67.7). Nineteen percent (n = 10/53) were dissatisfied with their outcome. CONCLUSIONS: ORIF for humeral diaphyseal nonunion was associated with a high rate of union. Routine BG was not required and avoided the risk of donor site morbidity. One in 5 patients were dissatisfied despite the majority achieving union. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Risk factors associated with delayed and aseptic nonunion following tibial diaphyseal fractures managed with intramedullary nailing.

AIMS: The primary aim of this study was to identify independent predictors associated with nonunion and delayed union of tibial diaphyseal fractures treated with intramedullary nailing. The secondary aim was to assess the Radiological Union Scale for Tibial fractures (RUST) score as an early predictor of tibial fracture nonunion. METHODS: A consecutive series of 647 patients who underwent intramedullary nailing for tibial diaphyseal fractures were identified from a trauma database. Demographic data, comorbidities, smoking status, alcohol consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and steroid use were documented. Details regarding mechanism of injury, fracture classification, complications, and further surgery were recorded. Nonunion was defined as the requirement for revision surgery to achieve union. Delayed union was defined as a RUST score < 10 at six months postoperatively. RESULTS: There were 41 nonunions (6.3%), of which 13 were infected (31.7%), and 77 delayed unions (11.9%). There were 127 open fractures (19.6%). Adjusting for confounding variables, NSAID use (odds ratio (OR) 3.50; p = 0.042), superficial infection (OR 3.00; p = 0.026), open fractures (OR 5.44; p < 0.001), and high-energy mechanism (OR 2.51; p = 0.040) were independently associated with nonunion. Smoking (OR 1.76; p = 0.034), open fracture (OR 2.82; p = 0.001), and high-energy mechanism (OR 1.81; p = 0.030) were independent predictors associated with delayed union. The RUST score at six-week follow-up was highly predictive of nonunion (sensitivity and specificity of 75%). CONCLUSION: NSAID use, high-energy mechanisms, open fractures, and superficial infection were independently associated with nonunion in patients with tibial diaphyseal fractures treated with intramedullary nailing. The six-week RUST score may be useful in identifying patients at risk of nonunion. Cite this article: Bone Jt Open 2021;2(4):227-235.

Closed reduction of glenohumeral dislocations with associated tuberosity fracture in the emergency department is safe.

AIM: A fracture of the tuberosity is associated with 16% of glenohumeral dislocations. Extension of the fracture into the humeral neck can occur during closed manipulation, leading some to suggest that all such injures should be managed under general anaesthesia in the operating theatre. The purpose of this study was to establish the safety of reduction of glenohumeral dislocations with tuberosity fractures in the emergency department (ED). PATIENTS AND METHODS: We reviewed 188 consecutive glenohumeral dislocations with associated tuberosity fractures identified from a prospective orthopaedic trauma database. Patient demographics, injury details, emergency department management and complications were recorded. The method of reduction, sedation, grade of clinician and outcome were documented. RESULTS: The mean age was 61 years (range 18-96 years) with 79 males and 109 females. The majority of injuries (146, 78%) occurred after a fall from standing height. Closed reduction under sedation in the ED was successful in 162 (86%) cases. Of the remainder, 22 (11%) failed closed reduction under sedation and subsequently went to theatre and 6 (3%) were deemed not suitable for ED manipulation. At presentation 35 (19%) patients had a nerve injury, of which 29 (90%) resolved spontaneously. Two iatrogenic fractures occurred during close manipulation, one in the ED and the other in the operating theatre. Therefore, the risk of iatrogenic propagation of the fracture into the proximal humerus neck was 0.5% if the reduction was performed in the ED, and 1% over-all. More than two attempted reductions predicted a failed ED reduction (P = 0.001). CONCLUSION: Closed reduction of glenohumeral dislocations with associated tuberosity fractures in the ED is safe, with a rate of iatrogenic fracture of 1%. These injuries should be managed by those with appropriate experience only after two adequate radiographic views. In cases where there is ambiguity over the integrity of the humeral neck, reduction should be delayed until multiplanar CT imaging has been obtained.

Brief report: Lymph node morphology in stage II colorectal cancer.

BACKGROUND: Colorectal cancer is one of the leading causes of cancer-associated morbidity and mortality worldwide. The local anti-tumour immune response is particularly important for patients with stage II where the tumour-draining lymph nodes have not yet succumbed to tumour spread. The lymph nodes allow for the expansion and release of B cell compartments such as primary follicles and germinal centres. A variation in this anti-tumour immune response may influence the observed clinical heterogeneity in stage II patients. AIM: The aim of this study was to explore tumour-draining lymph node histomorphological changes and tumour pathological risk factors including the immunomodulatory microRNA-21 (miR-21) in a small cohort of stage II CRC. METHODS: A total of 23 stage II colorectal cancer patients were included. Tumour and normal mucosa samples were analysed for miR-21 expression levels and B-cell compartments were quantified from Haematoxylin and Eosin slides of lymph nodes. These measures were compared to clinicopathological risk factors such as perforation, bowel obstruction, T4 stage and high-grade. RESULTS: We observed greater Follicle density in patients with a lower tumour T stage and higher germinal centre density in patients with higher pre-operative carcinoembryonic antigen levels. Trends were also detected between tumours with deficiency in mismatch repair proteins, lymphatic invasion and both the density and size of B-cell compartments. Lastly, elevated tumour miR-21 was associated with decreased Follicle and germinal centre size. CONCLUSION: Variation in B-cell compartments of tumour-draining lymph nodes is associated with clinicopathological risk factors in stage II CRC patients.

Combined renal and common hepatic artery denervation as a novel approach to reduce cardiometabolic risk: technical approach, feasibility and safety in a pre-clinical model.

BACKGROUND: Cardiovascular and metabolic regulation is governed by neurohumoral signalling in relevant organs such as kidney, liver, pancreas, duodenum, adipose tissue, and skeletal muscle. Combined targeting of relevant neural outflows may provide a unique therapeutic opportunity for cardiometabolic disease. OBJECTIVES: We aimed to investigate the feasibility, safety, and performance of a novel device-based approach for multi-organ denervation in a swine model over 30 and 90 days of follow-up. METHODS: Five Yorkshire cross pigs underwent combined percutaneous denervation in the renal arteries and the common hepatic artery (CHA) with the iRF Denervation System. Control animals (n = 3) were also studied. Specific energy doses were administered in the renal arteries and CHA. Blood was collected at 30 and 90 days. All animals had a pre-terminal procedure angiography. Tissue samples were collected for norepinephrine (NEPI) bioanalysis. Histopathological evaluation of collateral structures and tissues near the treatment sites was performed to assess treatment safety. RESULTS: All animals entered and exited the study in good health. No stenosis or vessel abnormalities were present. No significant changes in serum chemistry occurred. NEPI concentrations were significantly reduced in the liver (- 88%, p = 0.005), kidneys (- 78%, p < 0.001), pancreas (- 78%, p = 0.018) and duodenum (- 95%, p = 0.028) following multi-organ denervation treatment compared to control animals. Histologic findings were consistent with favourable tissue responses at 90 days follow-up. CONCLUSIONS: Significant and sustained denervation of the treated organs was achieved at 90 days without major safety events. Our findings demonstrate the feasibility of multi-organ denervation using a novel iRF Denervation System in a single procedure.

Contrast-Induced Rhabdomyolysis Occurring after ERCP in a Patient with Pancreatic Cancer: A Case Report.

OBJECTIVE: We present a patient with pancreatic cancer who developed weakness, acute renal failure and significantly raised creatine kinase levels post-ERCP and who was assessed as having contrast-induced rhabdomyolysis. RESULTS: The patient underwent haemofiltration and ultimately succumbed to his condition. CONCLUSION: Rhabdomyolysis is a potentially life-threatening condition which occurs because of damage to skeletal muscle, with release of myoglobin and electrolytes into the circulation. The mortality rate is 59% in severe cases, despite appropriate treatment. LEARNING POINTS: Iodine-based contrast can cause rhabdomyolysis by reducing blood flow to the muscle.Renal replacement therapy does not improve the mortality rate of rhabdomyolysis.<10% of patients present with the classic triad of myalgia, muscle weakness and tea-coloured urine; creatine kinase levels greater than 5 times the upper limit of normal are the gold standard for diagnosing rhabdomyolysis that is not related to statin use.

Operative repair of acute Achilles tendon rupture does not give superior patient-reported outcomes to nonoperative management.

AIMS: The aim was to compare long-term patient-reported outcome measures (PROMs) after operative and nonoperative treatment of acute Achilles tendon rupture in the context of a randomized controlled trial. METHODS: PROMs including the Short Musculoskeletal Function Assessment (SMFA), Achilles Tendon Total Rupture Score (ATRS), EuroQol five-dimension (EQ-5D), satisfaction, net promoter score and data regarding re-rupture, and venous thromboembolic rates were collected for patients randomized to receive either operative or nonoperative treatment for acute Achilles tendon rupture in a previous study. Of the 80 patients originally randomized, 64 (33 treated surgically, 31 nonoperatively) patients were followed up at a mean of 15.7 years (13.4 to 17.7). RESULTS: There was no statistically significant difference between operatively and nonoperatively treated patients, in SMFA Dysfunction Index (median 1.56 (interquartile range (IQR) 0 to 5.51) vs 1.47 (IQR 0 to 5.15); p = 0.289), SMFA Bother Index (2.08 (IQR 0 to 12.50) vs 0.00 (IQR 0 to 6.25); p = 0.074), ATRS (94 (IQR 86 to 100) vs 95 (IQR 81 to 100); p = 0.313), EQ-5D-5L (1 (IQR 0.75 to 1) vs 1 (IQR 0.84 to 1); p = 0.137) or EQ-5D health today visual analogue score (85 (IQR 72.5 to 95) vs 85 (IQR 8 to 95); p = 0.367). There was no statistically significant difference between operative and nonoperative groups in terms of satisfaction (84% vs 100%; p = 0.119) or willingness to recommend treatment to friends or family (79% vs 87%; p = 0.255). Four nonoperative patients and two in the operative group sustained a re-rupture (p = 0.306). CONCLUSION: Both patient groups reported good results at long-term follow-up. The findings give no evidence of superior long-term patient reported outcomes (as measured by the SMFA) for surgical treatment over nonoperative treatment. There was no demonstrable difference in other patient reported outcome measures, satisfaction, or re-rupture rates at long-term follow-up. Cite this article: Bone Joint J 2020;102-B(7):933-940.

Patterns of cartilage loss and anterior cruciate ligament status in end-stage osteoarthritis of the knee.

AIMS: This study aims to determine the proportion of patients with end-stage knee osteoarthritis (OA) possibly suitable for partial (PKA) or combined partial knee arthroplasty (CPKA) according to patterns of full-thickness cartilage loss and anterior cruciate ligament (ACL) status. METHODS: A cross-sectional analysis of 300 consecutive patients (mean age 69 years (SD 9.5, 44 to 91), mean body mass index (BMI) 30.6 (SD 5.5, 20 to 53), 178 female (59.3%)) undergoing total knee arthroplasty (TKA) for Kellgren-Lawrence grade ≥ 3 knee OA was conducted. The point of maximal tibial bone loss on preoperative lateral radiographs was determined as a percentage of the tibial diameter. At surgery, Lachman's test and ACL status were recorded. The presence of full-thickness cartilage loss within 16 articular surface regions (two patella, eight femoral, six tibial) was recorded. RESULTS: According to articular cartilage loss and ACL status, 195/293 (67%) were suitable for PKA or CPKA: medial unicompartmental knee arthroplasty (UKA) 97/293 (33%); lateral UKA 25 (9%); medial bicompartmental arthroplasty 31 (11%); lateral bicompartmental arthroplasty 12 (4%); bicondylar-UKA 23 (8%); and patellofemoral arthroplasty (PFA) seven (2%). The ACL was intact in 166 (55%), frayed in 82 (27%), disrupted in 12 (4%), and absent in 33 (11%). Lachman testing was specific (97%) but poorly sensitive (38%) for disrupted/absent ACLs. The point of maximal tibial bone loss showed good interclass correlation (ICC 0.797, 0.73 to 0.85 95% confidence interval (CI); p < 0.001) and was more posterior when the ACL was absent. Maximum tibial bone loss occurring at > 55% of the anterior to posterior distance predicted ACL absence with 93% sensitivity and 91% specificity (area under the curve 0.97 (0.94 to 0.99 95% CI; p < 0.001). CONCLUSION: ACL status can be reliably determined from a lateral radiograph using the location of maximal tibial bone loss. According to regions of cartilage loss and ACL status, two-thirds of patients with end-stage knee OA could potentially be treated with PKA or CPKA. Cite this article: Bone Joint J 2020;102-B(6):716-726.

Associations Between Mutations in MSH6 and PMS2 and Risk of Surveillance-detected Colorectal Cancer.

BACKGROUND & AIMS: Lynch syndrome is the most common inherited cause of colorectal cancer (CRC). Contemporary and mutation-specific estimates of CRC-risk in patients undergoing colonoscopy would optimize surveillance strategies. We performed a prospective national cohort study, using data from New Zealand, to assess overall and mutation-specific risk of CRC in patients with Lynch syndrome undergoing surveillance. METHODS: We performed a prospective study of 381 persons with Lynch syndrome in New Zealand (98 with Lynch-syndrome associated variants in MLH1, 159 in MSH2, 103 in MSH6, and 21 in PMS2). Participants were offered annual colonoscopy starting at age 25 y, and those who underwent 2 or more colonoscopies before December 31, 2017 were included in the final analysis. Patients with previous colonic resection, history of CRC or diagnosis of CRC at index colonoscopy were excluded. RESULTS: Study participants underwent 2061 colonoscopies during 2296 person-y; the median observation-period was 4.43 y and mean-age at enrollment was 43 y. Eighteen patients developed CRC (8 with variants in MLH1, 8 in MSH2, and 2 in MSH6) after a median follow-up period of 6.5 y (range 1-16 y). Eighty-three percent of patients had a surveillance colonoscopy in preceding 24 months before diagnosis of CRC; 94% were diagnosed with stage 0-II CRC and there was no CRC-related mortality. The overall-risk of developing CRC in the 5 y after first surveillance colonoscopy was 2.49% (95% CI, 1.18-5.23); cumulative risks for CRC in patients with Lynch syndrome-associated variants in MLH1, MSH2, or MSH6 by age 70 y were 17.7%, 17.8%, and 8.5%, respectively. Age-adjusted CRC-risk in patients with variants in MSH6 was lower than in MLH1 (hazard ratio, 0.2; 95% CI, 0.04-0.94; P = .02). Of patients with CRC, 33% had an adenomatous polyp resected from same segment in which a colorectal tumor later developed. CONCLUSIONS: The risk of CRC in patients with Lynch syndrome-associated mutations in MSH6 or PMS2 was significantly lower than in patients with mutations in MLH1. Incomplete adenomatous polyp resection might be responsible for one third of surveillance-detected CRCs.

Correlations between radiological classification systems and confirmed cartilage loss in severe knee osteoarthritis.

AIMS: Although knee osteoarthritis (OA) is diagnosed and monitored radiologically, actual full-thickness cartilage loss (FTCL) has rarely been correlated with radiological classification. This study aims to analyze which classification system correlates best with FTCL and to assess their reliability. METHODS: A prospective study of 300 consecutive patients undergoing unilateral total knee arthroplasty (TKA) for OA (mean age 69 years (44 to 91; standard deviation (SD) 9.5), 178 (59%) female). Two blinded examiners independently graded preoperative radiographs using five common systems: Kellgren-Lawrence (KL); International Knee Documentation Committee (IKDC); Fairbank; Brandt; and Ahlbäck. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). Intraoperatively, anterior cruciate ligament (ACL) status and the presence of FTCL in 16 regions of interest were recorded. Radiological classification and FTCL were correlated using the Spearman correlation coefficient. RESULTS: Knees had a mean of 6.8 regions of FTCL (SD 3.1), most common medially. The commonest patterns of FTCL were medial ± patellofemoral (143/300, 48%) and tricompartmental (89/300, 30%). ACL status was associated with pattern of FTCL (p = 0.023). All radiological classification systems demonstrated moderate ICC, but this was highest for the IKDC: whole knee 0.68 (95% confidence interval (CI) 0.60 to 0.74); medial compartment 0.84 (95% CI 0.80 to 0.87); and lateral compartment 0.79 (95% CI 0.73 to 0.83). Correlation with actual FTCL was strongest for Ahlbäck (Spearman rho 0.27 to 0.39) and KL (0.30 to 0.33) systems, although all systems demonstrated medium correlation. The Ahlbäck score was the most discriminating in severe knee OA. Osteophyte presence in the medial compartment had high positive predictive value (PPV) for FTCL, but not in the lateral compartment. CONCLUSION: The Ahlbäck and KL systems had the highest correlation with confirmed cartilage loss at TKA. However, the IKDC system displayed the best interobserver reliability, with favourable correlation with FTCL in medial and lateral compartments, although it was less discriminating in more severe disease. Cite this article: Bone Joint J 2020;102-B(3):301-309.

The sound of tablets during coating erosion, disintegration, deaggregation and dissolution.

This research aims to address a gap in our understanding of the mechanisms by which pharmaceutical tablets achieve highly reproducible and predictable drug release. The present industrial and regulatory practice is centred around tablet dissolution, i.e. what follows disintegration, yet the vast majority of problems that are found in formulation dissolution testing can be traced back to the erratic disintegration behaviour of the medicinal product. It is only due to the distinct lack of quantitative measurement techniques for disintegration analysis that this situation arises. Current methods involve costly, and time-consuming test equipment, resulting in a need for more simple, green and efficient methods which have the potential to enable rapid development and to accelerate routine solid drug formulation dissolution and disintegration testing. In this study, we present a novel approach to track several sequential tablet dissolution processes, including coating erosion, disintegration, deaggregation and dissolution using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS, in combination with minimal usage of UV spectroscopy, can effectively track these processes. The data also show that a solid oral dose formulation has an intrinsic acoustic signature which is specific to the method of manufacture and excipient composition.