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Multiple myeloma is a malignancy of blood cells that commonly metastasizes to bone. Metastasis to the acetabulum can cause significant patient distress due to pathological fractures that can be extremely painful and affects patients' ability to ambulate. The lytic lesions are unique and often require surgical management in order to restore normal anatomy to allow for weight bearing. A multidisciplinary approach is necessary to establish patient goals and optimize treatment plans. This report describes the presentation and treatment of an elderly patient with multiple myeloma and an unstable acetabular fracture with a large lytic lesion of the pelvis. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets the disease source at the RNA level and offers a promising alternative to therapies targeting downstream processes. To translate ASO-based therapies into a clinical success, it is crucial to overcome the challenges associated with off-target side effects and insufficient biological activity. In this regard, several chemical modifications and diverse delivery strategies have been explored. In this review, we systematically discuss the chemical modifications, mechanism of action, and optimized delivery strategies of several different classes of ASOs. Further, we highlight the recent advances made in development of ASO-based drugs with a focus on drugs that are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical applications. We also discuss various promising ASO-based drug candidates in the clinical trials, and the outstanding opportunity of emerging microRNA as a viable therapeutic target for future ASO-based therapies.

Background: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy., Methods: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41-86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094., Findings: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported., Interpretation: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092., Funding: Bristol-Myers Squibb, Biogen., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Extracellular tau is hypothesized to mediate the onset and progression of tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and a subset of frontotemporal lobar degenerations. A putative strategy for treating these disorders is to reduce extracellular tau levels using tau-directed immunotherapy. The results of the first-in-human study of BIIB092 (formerly BMS-986168/IPN007), a humanized monoclonal antibody that binds to N-terminal tau, are reported here. This randomized, double-blind, single ascending dose study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity profile of BIIB092 after a single intravenous infusion in healthy participants., Methods: Sixty-five participants were randomized to receive a single intravenous infusion of placebo or BIIB092 at doses of 21, 70, 210, 700, 2100, or 4200 mg (or 700 or 2100 mg for Japanese participants). Serial blood and cerebrospinal fluid samples were obtained for assessment of pharmacokinetic parameters and unbound N-terminal tau suppression., Results: There were no deaths, serious adverse events (AEs), severe AEs, or discontinuations due to an AE. The majority of AEs were mild. Serum BIIB092 concentrations increased in a dose-proportional manner and suppressed unbound cerebrospinal fluid N-terminal tau by 67%-97% at 28 days after dose, with doses of ≥210 mg producing persistent unbound N-terminal tau suppression over 12 weeks. Levels of cerebrospinal fluid N-terminal tau suppression were similar for Japanese and non-Japanese participants., Discussion: BIIB092 was generally safe and well tolerated after a single dose of up to 4200 mg, and up to 2100 mg in Japanese participants. BIIB092 exhibited a dose-dependent increase in the extent and duration of unbound N-terminal tau suppression.

This review describes the European Union and the US regulations applicable to food colours. Despite the different regulatory frameworks, the overall approach is similar, based on well-established risk-assessment procedures and risk-management measures. However, differences impacting free movement of goods can be found in the details and implementation of regulations. Using additives approved only in the US or in the EU implies that producers aiming to export need to adjust their product composition to the export market. Failure to comply may give rise to claims of adulteration, misbranding or non-compliance and rejection at the border or recall from the market. A careful comparison of the level of protection provided by the two sets of regulations, the criteria of good manufacturing practice (GMP) inspections and the certification requirements could be key to aligning the rules and to negotiating mutual recognition agreements. This review provides an extensive overview of the similarities and differences in regulating food colours in the EU and the US.

Self-expandable medical devices provide mechanical functionality at a specific location of the human body and are viable for minimal invasive procedures. Besides radiopaque markers and drug-eluting coatings, next generation self-expandable devices can be equipped with additional functionality, such as conductive and flexible electrodes, which enables chronic recording of bioelectrical signals, stimulating or ablating tissue. This promises new therapeutic options in various medical fields, among them in particular neuromodulation (e.g. deep brain stimulation), BioMEMS, radio frequency ablation, mapping or denervation. However, the fabrication of such multi-functional devices is challenging. For this study we have realized a 35 μm thick, superelastic NiTi thin film stent structure with six isolated electrodes on the outer circumference, each electrode connected to a contact pad at the end of the stent structure, using magnetron sputtering, UV lithography and wet chemical etching. Mechanical and electrical properties of the device during typical loading conditions, i.e. crimping, simulated pulsatile and electrochemical testing, were characterized and reveal promising results. For the fabrication of future multifunctional, minimal invasive medical devices, such as electroceuticals or other intelligent implants, NiTi thin film technology is therefore a versatile alternative to conventional fabrication routes.

The positive influence of crystallographic compatibility on the thermal transformation stability has been already investigated extensively in the literature. However, its influence on the stability of the shape memory effect or superelasticity used in actual applications is still unresolved. In this investigation sputtered films of a highly compatible TiNiCuCo composition with a transformation matrix middle eigenvalue of 1±0.01 are exposed to thermal as well as to superelastic cycling. In agreement with previous results the thermal transformation of this alloy is with a temperature shift of less than 0.1 K for 40 cycles very stable; on the other hand, superelastic degradation behaviour was found to depend strongly on heat treatment parameters. To reveal the transformation dissimilarities between the differently heat-treated samples, the microstructure has been analysed by transmission electron microscopy, in situ stress polarization microscopy and synchrotron analysis. It is found that good crystallographic stability is not a sufficient criterion to avoid defect generation which guarantees high superelastic stability. For the investigated alloy, a small grain size was identified as the determining factor which increases the yield strength of the composition and decreases the functional degradation during superelastic cycling.This article is part of the themed issue 'Taking the temperature of phase transitions in cool materials'., (© 2016 The Author(s).)

Background: The aim of this study was to analyze risk factors promoting development of recoarctation (Re-CoA) in neonates who survived aortic arch repair from an anterior approach., Methods: Fifty consecutive neonates with biventricular morphology and ductal-dependent lower body perfusion who were discharged home following aortic arch repair with cardiopulmonary bypass between 2000 and 2012 were retrospectively reviewed. Arch anatomy was either interruption (n = 10) or hypoplasia with coarctation (n = 40). Aortic arch reconstruction was performed by using patch material (bovine pericardium, n = 30, homograft, n = 10, or glutaraldehyde-treated autologous pericardium, n = 7), and three patients underwent direct end-to-side anastomosis. Antegrade cerebral and continuous myocardial perfusion was performed in 39 and 21 patients, respectively. Kaplan-Meier freedom from Re-CoA was calculated. Morphologic and perioperative data indicating increased risk of Re-CoA by univariate analysis were included in multivariate Cox regression analysis., Results: Mean follow-up was 5.3 ± 4.1 years. Re-CoA occurred in 13 patients and was treated successfully by balloon dilatation (n = 6) or surgery (n = 7). Freedom from Re-CoA after 1 and 5 years was 83 ± 5 and 79 ± 6%, respectively. Two patients died early after surgical repair of Re-CoA. The use of autologous pericardium for aortic arch augmentation was the only independent risk factor for development of Re-CoA (hazard ratio: 4.3 [95% confidence interval: 1.2-16.1]; p = 0.028)., Conclusion: Re-CoA following neonatal aortic arch surgery can be treated by balloon dilatation or surgery, if adequate. In this study, the risk for development of Re-CoA was independently increased by the use of autologous pericardium during initial arch repair., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Leaving an inter-atrial communication (IAC) open for left atrial decompression is often recommended in neonates with aortic arch obstruction undergoing primary repair. In this study, outcomes in these patients were compared to those with intact atrial septum after repair., Methods: Between 2000 and 2013, 53 consecutive neonates with severe aortic arch obstruction (hypoplasia: n = 45, interruption: n = 8) underwent primary repair from an anterior approach. Median age and weight were 8 days (range: 2-30) and 3.2 kg (range: 2.4-4.4), respectively. Cardiac morphology included a ventricular septal defect (VSD, large: n = 28, small: n = 7), malposition of great arteries (n = 10), and severe left ventricular outflow tract obstruction (LVOTO, n = 10). During corrective surgery IAC was closed (group-I, n = 37) or partially left-open (group-II, n = 16). Primary endpoints were hospital death, and re-intervention (surgery and/or balloon) due to aortic arch re-coarctation or recurrent LVOTO. Statistically significant variables by univariate analysis were incorporated in the corresponding multivariable regression model., Results: Regarding morphological discrepancies more patients in group-II presented with LVOTO (p = 0.05), or the combination of arch hypoplasia, intact ventricular septum and normal ventriculo-arterial connection (p = 0.017). Hospital mortality was 8.1% in group-I and 37.5% in group-II (p = 0.016). Re-intervention was performed in 13 patients (group-I: n = 6 vs. group-II: n = 7) due to aortic arch re-coarctation (n = 12) and/or recurrent LVOTO (n = 3), and resulted in a Kaplan-Meier freedom from re-intervention of 87 ± 6% and 79 ± 8% in group-I, and 64 ± 14% and 64 ± 14% in group-II after 1 and 5 years, respectively (p = 0.016). Multivariate analysis revealed LVOTO as an independent risk factor for hospital death (p = 0.042), whereas both LVOTO and left-open IAC (p = 0.001 and 0.01) were independent risk factors for re-intervention., Conclusions: A left-open IAC increases risk of re-intervention at the left heart aorta complex. Sustained left-to-right shunting on atrial level seems to induce preload reduction of the often restrictive left ventricle leading to decreased aortic blood flow.

Purpose: To investigate whether amifostine can reduce radiation hematotoxicity., Patients and Methods: Seventy-three patients undergoing radiotherapy for squamous cell carcinoma of the head and neck at the university clinics of Freiburg, Heidelberg, and Erlangen were evaluated. All received 60 Gy (50-70 Gy) at 5 x 2 Gy fractions per week employing standard techniques. Thirty-five were randomized to receive 200 mg/m(2) amifostine i.v. 30 min before radiation; 38 served as control patients. Blood counts (total n = 501) were determined before, during, and while completing radiotherapy. Changes of leukocyte, platelet, and hemoglobin levels were determined and compared using the t test., Results: The blood hemoglobin level and the platelet count were not affected by irradiation, for either the amifostine-treated or control patients. Similarly, the leukocyte counts of amifostine-treated patients did not change during irradiation. However, control patients experienced a decrease in leukocyte count from 8.1 x 10(3)/mm(3) to 5.8 x 10(3)/mm(3) (difference: 2.3 x 10(3)/mm(3)). This seems to be line specific: Whereas amifostine does not affect lymphocyte count, a radiation-induced decrease of neutrophil granulocytes seems to be prevented., Conclusion: Amifostine protects from radiation hematotoxicity, particularly affecting the granulocytopoiesis. These data confirm results from our former study.

Background: Radiotherapy--even of small volumes--can decrease leukocyte counts. We examined whether the radio-protector amifostine can reduce this hematotoxicity., Patients and Methods: Twenty-six patients (Table 1) undergoing radiotherapy for squamous cell carcinoma of the head and neck were evaluated. All were given 60 (to 70) Gy 5 x 2 Gy per week in standard radiation techniques. Thirteen patients are randomized to receive 200 mg/m2 amifostine i.v., 30 minutes before radiation. Blood counts and differentials were determined before, during and following radiotherapy. Differences of these parameters are calculated and compared by t-test., Results: The blood hemoglobin and the thrombocyte levels did not change during the radiotherapy course, neither for the amifostine treated, nor the control patients. Similarly the leukocyte counts of amifostine treated patients did not change during irradiation. The control patients, however, had a decrease of leukocytes from 8.4 to 6.0 x 10(3)/microliter, p = 0.03 (Table 2), and the reduction of the neutrophilic granulocyte count was more impressive for these patients., Conclusion: In this explorative study amifostine diminished radiation induced leukocyte toxicity.