The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland.

This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. INTRODUCTION: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. METHODS: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. RESULTS: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. CONCLUSION: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.

Host guest chemistry and supramolecular doping in triphenylamine-based covalent frameworks on Au(111).

The post-synthetic modification of covalent organic frameworks (COFs) via host-guest chemistry is an important method to tailor their electronic properties for applications. Due to the limited structural control in the assembly of two-dimensional surface-supported COFs, supramolecular networks are traditionally used at present for host-guest experiments on surfaces, which lack structural and thermal stability, however. Here, we present a combined scanning tunneling microscopy and density functional theory study to understand the host-guest interaction in triphenylamine-based covalently-linked macrocycles and networks on Au(111). These triphenylamine-based structures feature carbonyl and hydrogen functionalized pores that create preferred adsorption sites for trimesic acid (TMA) and halogen atoms. The binding of the TMA through optimized hydrogen-bond interactions is corroborated by selective adsorption positions within the pores. Band structure calculations reveal that the strong intermolecular charge transfer through the TMA bonding reduces the band gap in the triphenylamine COFs, demonstrating the concept of supramolecular doping by host-guest interactions in surface-supported COFs. Halogen atoms selectively adsorb between two carbonyl groups at Au hollow sites. The mainly dispersive interaction of the halogens with the triphenylamine COF leads to a small downshift of the bands. Most of the halogens change their adsorption position selectively upon annealing near the desorption temperature. In conclusion, we demonstrate evidence for supramolecular doping via post-synthetic modification and to track chemical reactions in confined space.

Increased rates of cetuximab reactions in tick prevalent regions and a proposed protocol for risk mitigation.

BACKGROUND: Cetuximab is an anti-epidermal growth factor receptor mouse-human chimeric monoclonal antibody used to treat advanced colorectal cancers. Initial data suggest that severe infusion reactions occurred in 4.5%, many on first exposure. The majority of those with anaphylactic reactions possess predeveloped IgE antibodies to galactose-alpha-1,3-galactose. It is thought that the vector for preexposure to alpha-gal is antigen inoculation via tick bites. This retrospective study reviews the experience of two community cancer centers in high tick exposure areas in Sydney with cetuximab anaphylaxis and proposes a protocol to avoid this. METHOD: Severe cetuximab infusion reactions occurring in the Northern Cancer Institute Frenchs Forest and St Leonards clinics, Sydney, from May 2014 to February 2019 were recorded. Area of residence was then compared to areas of known high tick prevalence. RESULTS: A total of 87 patients received cetuximab in this period. Six patients (6.9%) experienced at least a grade 3 reaction, three females, age range 41-72 years (median 57.5 years). All were receiving cetuximab for metastatic colorectal cancer and their anaphylaxis occurred with the first infusion in all cases. CONCLUSION: These cases support the existing theory of increased rates of cetuximab anaphylaxis in areas of high tick prevalence. Given this, we recommend the following protocol for patients being considered for cetuximab therapy: known mammalian meat allergy as an absolute contraindication; all patients receiving cetuximab should have RAST (ImmunoCAP® ) testing for alpha-gal specific-IgE-specific antibodies before first infusion and those who test positive to be considered alternate therapy.

Binary supramolecular networks of bridged triphenylamines with different substituents and identical scaffolds.

Based on scanning tunneling microscopy experiments combined with density functional theory, we report the formation and the electronic structure of porous binary supramolecular networks on Au(111). The two triphenylamine derivatives with identical scaffolds intermix due to a maximization of the overall number of H-bonds instead of an optimization of the H-bond strength in the bonding motif. The HOMO-LUMO gap is defined by both molecules, which is typical for electron donor-acceptor networks.

Hierarchical on-surface synthesis and electronic structure of carbonyl-functionalized one- and two-dimensional covalent nanoarchitectures.

The fabrication of nanostructures in a bottom-up approach from specific molecular precursors offers the opportunity to create tailored materials for applications in nanoelectronics. However, the formation of defect-free two-dimensional (2D) covalent networks remains a challenge, which makes it difficult to unveil their electronic structure. Here we report on the hierarchical on-surface synthesis of nearly defect-free 2D covalent architectures with carbonyl-functionalized pores on Au(111), which is investigated by low-temperature scanning tunnelling microscopy in combination with density functional theory calculations. The carbonyl-bridged triphenylamine precursors form six-membered macrocycles and one-dimensional (1D) chains as intermediates in an Ullmann-type coupling reaction that are subsequently interlinked to 2D networks. The electronic band gap is narrowed when going from the monomer to 1D and 2D surface-confined π-conjugated organic polymers comprising the same building block. The significant drop of the electronic gap from the monomer to the polymer confirms an efficient conjugation along the triphenylamine units within the nanostructures.

Optically pure, monodisperse cis-oligodiacetylenes: aggregation- induced chirality enhancement.

Conformational changes in the conjugated backbone of poly- and oligodiacetylenes (PDAs and ODAs) play an important role in determining the electronic properties of these compounds. At the same time, conformational changes can also result in a folded structure that shows helical chirality. Using d-camphor as a chiral building block, we have designed a high-yielding, iterative synthesis of monodisperse, optically pure cis-oligodiacetylenes (ODAs). cis-ODAs up to the tridecamer have been formed, which is the longest monodisperse cis-ODA reported to date. UV/Vis spectroscopy suggests a large effective conjugation length in THF, likely the result of a linear, planar conformation in this solvent. High-resolution STM/AFM measurements of the nonamer cast from THF onto HOPG show a linear structure. In iPrOH, circular dichroism (CD) spectra suggest the formation of chiral aggregates for ODAs with at least nine d-camphor units, based on a strong CD response.

Management of Morel-Lavallee Lesion Associated with Pelvic and/or Acetabular Fractures.

OBJECTIVE: Management of Morel-Lavallee soft tissue lesion (MLL) in patients with associated pelvic and/or acetabular fractures is still under discussion. Especially, the sequence of treatment of MLL soft tissue management and osteosynthesis of pelvic and acetabular injury remains controversial. METHODS: We report all consecutive patients with MLL associated with pelvic ring and/or acetabular fractures during an 8-year period at our hospital. Surgical access and techniques were analyzed concerning complications and outcome. RESULTS: Altogether, 20 patients were included in the study. One patient was treated conservatively and MLL healed without complications; 19 patients had an operative treatment of MLL. In 15 patients debridement was performed within one day after injury and in four patients with delay of 5 days at least. Ten patients had surgery for an associated pelvic ring or acetabular fracture. In four of them MLL was operated before, in six patients simultaneously to osteosynthesis. In three patients, the same surgical approach for osteosynthesis and debridement of MLL was used; none of them showed postoperative complications. Altogether, in nine operated patients (47.4%) MLL healed without any complications. Nine operated patients presented prolonged wound healing, however, during long term follow-up, all patients showed complete healing of the MLL. One patient died during resuscitive surgical procedures. CONCLUSIONS: We recommend debridement for early and delayed treatment of MLL. Osteosynthesis during first debridement may be performed without adverse outcome. Identical surgical access for both procedures can be used. In case of repeated surgical debridement VAC(®) therapy may be a helpful tool for dead space reduction and wound conditioning.

Binding of bilirubin and bromosulphthalein to albumin: implications for understanding the pathophysiology of liver failure and its management.

The binding/transporting functions of albumin provide the rationale for using albumin dialysis (e.g., molecular adsorbents recirculating system [MARS]) in liver failure. This study investigates these properties in vitro, validating the findings in vivo. In vitro bromosulphthalein (BSP) and bilirubin-spiked plasma were dialyzed against albumin and sampled. In vivo serum biochemistry was analyzed in: 7 MARS-treated liver failure patients; 98 MARS-treated patients from the MARS Registry; and 8 patients receiving albumin infusion. In vitro BSP concentrations did not equilibrate, but the molar ratio of BSP to albumin (C(BSP)/C(alb)) did, with no subsequent transmembrane transport, suggesting that the C(BSP)/C(alb) gradient (rather than simple diffusion) drives BSP transport. Bilirubin was transported similarly. In vivo serum bilirubin reduction during MARS sessions (n = 26) correlated with pre-treatment bilirubin (r = 0.42), but better (r = 0.85) with pre-treatment molar ratio of bilirubin to albumin (C(bilirubin)/C(alb)). The strongest correlation was between C(bilirubin)/C(alb) reduction and pre-treatment C(bilirubin)/C(alb) (r = 0.9). A similar pattern was observed in the MARS Registry patients. After albumin infusion (n = 8), both serum albumin and bilirubin increased, while C(bilirubin)/C(alb) remained unchanged. C(bilirubin)/C(alb) appears to be important in albumin dialysis, and generally in liver disease patients, reinforcing the importance of the toxin-binding functions of albumin in liver disease.

Equipment review: the molecular adsorbents recirculating system (MARS).

The molecular adsorbents recirculating system (MARS) is a form of artificial liver support that has the potential to remove substantial quantities of albumin-bound toxins that have been postulated to contribute to the pathogenesis of liver cell damage, haemodynamic instability and multi-organ failure in patients with acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF). These toxins include fatty acids, bile acids, tryptophan, bilirubin, aromatic amino acids and nitric oxide. Data from controlled clinical trials are limited so far. One of two studies performed on small numbers of patients with AoCLF suggest a survival benefit, but no controlled data are available in the ALF setting. Our preliminary experience with MARS therapy, instituted late in the clinical course of five patients with severely impaired liver function, including three with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease, indicates some clinical efficacy. However, the overall survival rate (1 of 5; 20%) remained poor. More data obtained from larger cohorts of patients enrolled in randomised controlled studies will be required in both the AoCLF and ALF settings to identify categories of liver failure patients who might benefit most from MARS treatment, to ascertain the most appropriate timing of intervention and to determine the overall impact on outcome, including cost-effectiveness.

Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis.

BACKGROUND/AIMS: The mortality of patients with severe acute alcoholic hepatitis (AH) remains high, leading to interest in the use of extracorporeal liver support. The molecular adsorbents recirculating system (MARS) is a liver support device based upon a hollow fibre module in which the patient's blood is dialyzed across an albumin-impregnated membrane. The aim of this paper is to assess the safety, efficacy and feasibility of using MARS in patients with severe AH. METHODS: Eight patients (all encephalopathic; hepatorenal syndrome: Type 1, five patients; Type 2, two patients) were treated with MARS. Clinical, biochemical and haemodynamic assessments were done. RESULTS: Five patients were discharged from hospital, and four are alive at 3 months of follow-up, compared with an estimated survival of about 20%. There were significant improvement in serum bilirubin (P=0.008), creatinine (P=0.02), prothrombin time (P=0.04), and grade of encephalopathy (P=0.05). Sustained improvements in mean arterial pressure, systemic vascular resistance and cardiac output were observed. Thrombocytopaenia was the only MARS-related adverse event observed. CONCLUSIONS: MARS resulted in improved liver biochemistry, cardiovascular haemodynamics, renal function and encephalopathy in patients with severe AH, with an apparent reduction in mortality. On this basis, a multi-centre, randomized clinical trial has been initiated.

Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease.

Wilson's disease presenting as acute liver failure (ALF) is potentially fatal, and liver transplantation (LTx) is the only option. We report two patients with Wilson's disease and ALF treated with the Molecular Adsorbents Recirculating System (MARS). Both patients fulfilled criteria for poor prognosis. Because LTx was not available immediately in either case, MARS was used as a bridge to LTx. In Case 1, serum bilirubin decreased from 803 to 425 micromol/L after 3 treatments, but increased to 656 micromol/L during a break, decreasing again to 457 micromol/L with further treatment. Serum copper decreased from 53.7 micromol/L, to 35.8 micromol/L after first treatment session, and 17.4 micromol/L at treatment completion. In Case 2, MARS treatment over 2 weeks reduced serum bilirubin from 1200 to 450 micromol/L and copper from 35 to 13 micromol/L with marked improvement in encephalopathy and reduction in ammonia (59 to 34 micromol/L). Both patients were successfully bridged to LTx (days 9 and 28, respectively). Analysis of albumin-dialysate from the MARS circuit suggested that copper removal occurred mostly in the first few hours of treatment, partly being adsorbed by albumin and partly by the MARSFlux membrane (Teraklin AG, Rostock, Germany). These data suggest that MARS removes copper efficiently and can be used to bridge patients with Wilson's disease and ALF to LTx.

Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry.

Extracorporeal liver support using the MARS recently has shown remarkable results in several trials. This study aims to extend the basis for analyses by making available the worldwide data with help of an international registry. One hundred and seventy six patients were analysed, main indications are acute-on-chronic liver failure (56%), acute liver failure (22%), primary graft dysfunction (15%), liver failure post liver surgery (4%) and miscellaneous (3%). The predicted survival within the first group based on a mean MELD score of 30.4 pts. and a mean Child score of 12.6 pts. was quite limited. The data suggest an improved survival accompanied by significant improvements of hepatic encephalopathy, mean arterial pressure, serum bilirubin level, creatinine, urea, albumin, INR, ammonia and MELD score. The results are confirming observations of other trials before which have shown MARS therapy to be an effective and safe extracorporeal liver support in liver failure.

Clinical outcome of edema-like bone marrow abnormalities of the foot.

PURPOSE: To evaluate the clinical outcome of edema-like bone marrow abnormalities seen on magnetic resonance (MR) images of the foot when their cause is unknown. MATERIALS AND METHODS: The clinical outcome of 31 patients (15 female patients, 16 male patients; mean age, 51; range, 10-79 years) with edema-like bone marrow abnormalities on MR images of the foot was determined. The relevance of three different edema patterns was compared: (a) exclusively ill-defined edema-like zones, (b) edema-like zones plus well-defined necrosis-like zones, and (c) edema-like zones plus linear structures indicating possible fractures. The different edema patterns were compared with persistence of pain. RESULTS: Fifty-four percent of all patients had pain persisting after 1 year, as calculated with the Kaplan-Meier method. The duration of pain in the various subgroups varied significantly (P =.049, log-rank test). The subgroup of patients with a well-defined necrosis-like zone had substantially longer-lasting pain than those with edema-like abnormalities only (n = 16) (P =.065). Only one of seven patients with a well-defined necrosis-like zone (n = 7) was pain free after 1 year. Conversely, patients with possible stress fracture (n = 8) had shorter pain compared with those with edema-like abnormalities only (P =.036); six of eight patients were pain free after 1 year. CONCLUSION: Edema-like bone marrow abnormalities of the foot predict long-lasting pain. Analysis of the image patterns of such abnormalities allows prediction of the clinical outcome to a certain degree.