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.

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.

Combination of laser microdissection, 2D-DIGE and MALDI-TOF MS to identify protein biomarkers to predict colorectal cancer spread.

Biomarkers are urgently required to support current histological staging to provide additional accuracy in stratifying colorectal cancer (CRC) patients according to risk of spread to properly assign adjuvant chemotherapy after surgery. Chemotherapy is given to patients with stage III to reduce the risk of recurrence but is controversial in stage II patients. Up to 25% of stage II patients will relapse within 5 years after tumor removal and when this occurs cure is seldom possible. The aim of this study was to identify protein biomarkers to stratify risk of spread of CRC patients. Laser micro-dissection was used to isolate cancer cells from primary colorectal tumors of stage II patients which did or did not metastasize within 5 years after surgical resection. Protein expression differences between two groups of tumors were profiled by 2D-DIGE with saturation CyDye labeling and identified using MALDI-TOF mass spectrometry. Evaluation of protein candidates was conducted using tissue micro array (TMA) immunohistochemistry on 125 colorectal tumor tissue samples of different stages. A total of 55 differentially expressed proteins were identified. Ten protein biomarkers were chosen based on p value and ratio between non metastasized and metastazised groups and evaluated on 125 tissues using TMA immunohistochemistry. Expression of HLAB, protein 14-3-3ß, LTBP3, ADAMTS2, JAG2 and NME2 on tumour cells was significantly associated with clinical parameters related to tumour progression, invasion and metastasis. Kaplan-Meier survival curve showed strong expression of six proteins was associated with good CRC specific survival. Expression of HLAB, ADAMTS2, LTBP3, JAG2 and NME2 on tumour cells, was associated with tumour progression and invasion, metastasis and CRC specific survival may serve as potential biomarkers to stratify CRC patients into low and high risk of tumour metastasis. Combined methods of laser microdissection, 2D DIGE with saturation labelling and MALDI-TOF MS proved to be resourceful techniques capable of identifying protein biomarkers to predict risk of spread of CRC to liver.

Fracture in drug-eluting stents increases focal intimal hyperplasia in the atherosclerosed rabbit iliac artery.

OBJECTIVES: Drug-eluting stent (DES) strut fracture (SF) is associated with higher incidence of In-stent restenosis (ISR)-return of blockage in a diseased artery post stenting-than seen with bare metal stents (BMS). We hypothesize that concomitance of drug and SF leads to greater neointimal response. BACKGROUND: Controlled release of therapeutic agents, such as sirolimus and its analogs, or paclitaxel from has reduced tissue based DES failure modes compared to BMS. ISR is dramatically reduced and yet the implications of mechanical device failure is magnified. METHODS: Bilateral Xience Everolimus-eluting stents (EES) were implanted in 20 New Zealand White rabbits on normal (n = 7) or high fat (HF)/high cholesterol (HC) (n = 13) diets. Implanted stents were intact or mechanically fractured. Everolimus concentration was as packaged or pre-eluted. After 21 days, stented vessels were explanted, resin embedded, MicroCT scanned, and analyzed histomorphometrically. RESULTS: Fractured EES were associated with significant (P < 0.05) increases in arterial stenosis and neointimal formation and lower lumen-to-artery area ratios compared to intact EES. Hyperlipidemic animals receiving pre-eluted EES revealed no significant difference between intact and fracture groups. CONCLUSIONS: SF increases intimal hyperplasia, post EES implant, and worse with more advanced disease. Pre-eluted groups, reflective of BMS, did not show significant differences, suggesting a synergistic effect of everolimus and mechanical injury, potentially explaining the lack of SF reports for BMS. Here, we report that ISR has a higher incidence with SF in EES, the clinical implication is that patients with SF after DES implantation merit careful follow-up.

An Overview on the Considerations for the Planning of Nonclinical Necropsies for Medical Device Studies.

The terminal collection and histological processing of medical devices is an expensive, labor-, and material-intensive endeavor, which requires adequate experience, innovation, and preparation for success. It is also an exciting endeavor that continually challenges, intellectually engages, and improves the skills and knowledge of the pathologist. Awareness of the importance of the medical device pathologist's involvement, communication, and oversight throughout the development, implementation, and execution of a nonclinical assessment of a medical device is in the best interest of the test facility, the histopathology laboratory, the pathologist, the sponsor, and, ultimately, the patients. This article serves to present as a primer of key considerations for the approach and conduct of "nontoxicological" studies, defined as studies involving animal models of deployment or implantation of medical devices as well as surgical animal models.

Preclinical Evaluation of Mesh Implants: The Pathologist's Perspective.

Surgical and laparoscopic implantation of mesh devices is on the rise for a variety of applications. The complexity and range of evolving mesh designs calls for consistent and detailed pathologic evaluation in determining host responses and assessing overall safety. This review addresses the components of evaluation of mesh implants in animal models, with emphasis on histologic parameters, semiquantitative scoring matrices, and morphometric analyses that have been specifically adapted to this class of implants. Necropsy assessment should include implant persistence, architecture, and associated host responses such as exudation and adhesions. Microscopic evaluation should focus on primary relevant responses such as bioresorption, integration/tissue ingrowth, neovascularization, and inflammation. Selection of the best means of processing and evaluation can be complicated, as meshes may include one or more biologic components (e.g., collagen), synthetic polymer fibers, coatings, and other molecules. The architecture of some meshes can influence tissue responses and complicate sampling, sectioning, and evaluation. Recognition of specific study objectives and knowledge of anticipated responses helps to determine the appropriate histologic or immunochemical stains, while understanding of mesh composition and anticipated persistence in tissue determines the suitability of paraffin or resin embedding, and both guide the evaluation of mesh devices in the preclinical setting.

Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter.

BACKGROUND AND OBJECTIVE: Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side-effect profiles are poorly understood. METHODS: Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post-injection. RESULTS: Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose-limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)(0-5d) 20- to 50-fold lower than the AUC(0-∞) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post-injection, bronchial PTX tissue concentrations were above a 10-nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX. CONCLUSION: Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow-up period.

Percutaneous Hepatic Perfusion With Filtered Melphalan for Localized Treatment of Metastatic Hepatic Disease: A Risk Assessment.

Regional therapies for metastatic liver disease have garnered interest in recent years due to technological advances in drug delivery. A percutaneous hepatic perfusion (PHP) using a newly developed generation 2 (GEN2) filtration system was designed to mitigate systemic toxicity and cardiovascular risk associated with hepatic blood filtration during hepatic artery infusion of the chemotherapy drug melphalan. The GEN2 system was evaluated in healthy swine, and plasma samples were assessed for clinical chemistry, melphalan toxicokinetics (TK), inflammatory cytokines, catecholamines, hematological, and cardiac biomarkers. Cardiovascular safety was assessed by echocardiography, electrocardiogram, and telemetry. Toxicology parameters included clinical signs, body weight, gross pathology, and histopathology. There were no treatment-related deaths associated with the PHP procedure with GEN2 filtration, and all animals survived to scheduled necropsy. Assessment of the pharmacokinetic/TK plasma concentrations of melphalan demonstrated that the GEN2 filter was able to extract melphalan from blood with high efficiency and reduce melphalan exposure in the systemic circulation. The hemodynamic, immunosuppressive, immunotoxic, cardiotoxic, and histopathologic effects of melphalan were limited. The significant hemodynamic challenge imposed by filtration resulted in a compensatory tachycardia with supranormal left ventricular function, although no wall motion abnormalities were detected and left ventricular function remained normal. Catecholamines decreased and then quickly rebounded during washout. Transient and reversible effects of treatment on cardiac enzymes, catecholamines, and cytokines and reversible hemodynamic effects without cardiac damage indicated that PHP with melphalan was not cardiotoxic or immunotoxic under the conditions tested, due to high efficiency of the filtration system limiting exposure of melphalan to the systemic circulation.

Medium-term patient-reported outcomes after total hip replacement for displaced hip fractures.

INTRODUCTION: The aim of the present study was to define the medium-term outcomes following total hip replacement (THR) for hip fracture. METHODS: We prospectively followed up 92 patients who underwent THR for a displaced hip fracture over a 3-year period between 2007 and 2010. These patients were followed up at 5 years using the Oxford Hip Score, Short-Form 12 (SF-12) questionnaire and satisfaction questionnaire. These outcomes were compared to the short-term outcomes previously reported at 2 years to determine any significant differences. RESULTS: Mean follow-up was at 5.4 years with a mean age at follow-up of 76.5 years. Seventy-four patients (80%) responded. Patients reported excellent functional outcomes and satisfaction (mean Oxford Hip Score 40.3; SF-12 Physical Health Composite Score 44.0; SF-12 Mental Health Composite Score 46.2; mean satisfaction 90%). The rates of dislocation (2%), deep infection (2%) and revision (3%) were comparable to those quoted for elective THR. When compared with 2-year follow-up, there were no statistically significant adverse changes in outcome parameters. CONCLUSIONS: Medium-term outcomes for THR after hip fracture in fit older patients are excellent, and these results demonstrate that the early proven benefits of this surgery are sustained into the midterm.

GM1-gangliosidosis in American black bears: clinical, pathological, biochemical and molecular genetic characterization.

G(M1)-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal ß-galactosidase. We have identified seven American black bears (Ursus americanus) found in the Northeast United States suffering from G(M1)-gangliosidosis. This report describes the clinical features, brain MRI, and morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of a G(M1)-mouse. The bears presented at ages 10-14 months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T(2)-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of the brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid ß-galactosidase activity in cultured skin fibroblasts was only 1-2% of control values. In the brain, ganglioside-bound sialic acid was increased more than 2-fold with G(M1)-ganglioside predominating. G(A1) content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in the G(M1)-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the G(M1) mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T(1042) to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several black bears with G(M1)-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population.

Autologous osteochondral mosaicplasty or TruFit plugs for cartilage repair.

PURPOSE: Autologous osteochondral mosaicplasty and TruFit Bone graft substitute plugs are methods used to repair symptomatic articular cartilage defects in the adult knee. There have been no comparative studies of the two techniques. METHODS: This retrospective study assessed functional outcome of patients using the EQ-5D, Knee Injury and Osteoarthritis Outcome Score (KOOS) and Modified Cincinnati scores at follow-up of 1-5 years. RESULTS: There were 66 patients in the study (35 TruFit and 31 Mosaicplasty): 44 males and 22 females with a mean age of 37.3 years (SD 12.6). The mean BMI was 26.8. Thirty-six articular cartilage lesions were due to trauma, twenty-six due to osteochondritis dissecans and three due to non-specific degenerative change or unknown. There was no difference between the two groups age (n.s.), sex (n.s.), BMI (n.s.), defect location (n.s.) or aetiology (n.s.). The median follow-up was 22 months for the TruFit cohort and 30 months for the mosaicplasty group. There was no significant difference in the requirement for re-operation (n.s). Patients undergoing autologous mosaicplasty had a higher rate of returning to sport (p = 0.006), lower EQ-5D pain scores (p = 0.048) and higher KOOS activities of daily living (p = 0.029) scores. Sub-group analysis showed no difference related to the number of cases the surgeon performed. Patients requiring re-operation had lower outcome scores regardless of their initial procedure. CONCLUSION: This study demonstrated significantly better outcomes using two validated outcome scores (KOOS, EQ-5D), and an ability to return to sport in those undergoing autologous mosaicplasty compared to those receiving TruFit plugs. LEVEL OF EVIDENCE: IV.

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.

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.

Potentiation of azole antifungals by 2-adamantanamine.

Azoles are among the most successful classes of antifungals. They act by inhibiting α-14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5% are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC. We reasoned that compounds affecting a different target may potentiate azoles to produce increased killing and an antibiofilm therapeutic. 2-Adamantanamine (AC17) was identified in a screen for compounds potentiating the action of miconazole against biofilms of Candida albicans. AC17, a close structural analog to the antiviral amantadine, did not affect the viability of C. albicans but caused the normally fungistatic azoles to become fungicidal. Transcriptome analysis of cells treated with AC17 revealed that the ergosterol and filamentation pathways were affected. Indeed, cells exposed to AC17 had decreased ergosterol contents and were unable to invade agar. In vivo, the combination of AC17 and fluconazole produced a significant reduction in fungal tissue burden in a guinea pig model of cutaneous candidiasis, while each treatment alone did not have a significant effect. The combination of fluconazole and AC17 also showed improved efficacy (P value of 0.018) compared to fluconazole alone when fungal lesions were evaluated. AC17 is a promising lead in the search for more effective antifungal therapeutics.

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.

"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.

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.

Synthesis and serotonin transporter activity of 1,3-bis(aryl)-2-nitro-1-propenes as a new class of anticancer agents.

Structural derivatives of 4-MTA, an illegal amphetamine analogue have been previously shown to have anticancer effects in vitro. In this study we report the synthesis of a series of novel 1,3-bis(aryl)-2-nitro-1-propene derivatives related in structure to 4-MTA. A number of these compounds containing a classic nitrostyrene structure are shown to have antiproliferative activities in vitro in a range of malignant cell lines, particularly against Burkitt's lymphoma derived cell lines, whilst having no effect on 'normal' peripheral blood mononuclear cells. Such effects appear to be independent of the serotonin transporter, a high affinity target for amphetamines and independent of protein tyrosine phosphatases and tubulin dynamics both of which have been previously associated with nitrostyrene-induced cell death. We demonstrate that a number of these compounds induce caspase activation, PARP cleavage, chromatin condensation and membrane blebbing in a Burkitt's lymphoma derived cell line, consistent with these compounds inducing apoptosis in vitro. Although no specific target has yet been identified for the action of these compounds, the cell death elicited is potent, selective and worthy of further investigation.