Clinical Features of 24 Patients With Rebound‐Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases

We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty‐four postmenopausal women with vertebral fracture(s) after denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last denosumab injection. Eighty‐three percent of the patients were treatment naïve, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut‐off of 2 years, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients. © 2017 American Society for Bone and Mineral Research.     

The truth-telling motor cortex: response competition in M1 discloses deceptive behaviour

Neural circuits associated with response conflict are active during deception. Here we use transcranial magnetic stimulation to examine for the first time whether competing responses in primary motor cortex can be used to detect lies. Participants used their little finger or thumb to respond either truthfully or deceitfully regarding facial familiarity. Motor-evoked-potentials (MEPs) from muscles associated with both digits tracked the development of each motor plan. When preparing to deceive, the MEP of the non-responding digit (i.e. the plan corresponding to the truth) exceeds the MEP of the responding digit (i.e. the lie), whereas a mirror-reversed pattern occurs when telling the truth. This give away response conflict interacts with the time of stimulation during a speeded reaction period. Lies can even activate digit-specific cortical representations when only verbal responses are made. Our findings support neurobiological models which blend cognitive decision-making with motor programming, and suggest a novel index for discriminating between honest and intentionally false facial recognition.     

Hydrophilic Random Cationic Copolymers as Polyplex-Formation Vectors for DNA

Research on the improvement and fabrication of polymeric systems as non-viral gene delivery carriers is required for their implementation in gene therapy. Random copolymers have not been extensively utilized for these purposes. In this regard, double hydrophilic poly[(2-(dimethylamino) ethyl methacrylate)-co-(oligo(ethylene glycol) methyl ether methacrylate] [P(DMAEMA-co-OEGMA)] random copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The copolymers were further modified by quaternization of DMAEMA tertiary amine, producing the cationic P(QDMAEMA-co-OEGMA) derivatives. Fluorescence and ultraviolet–visible (UV–vis) spectroscopy revealed the efficient interaction of copolymers aggregates with linear DNAs of different lengths, forming polyplexes, with the quaternized copolymer aggregates exhibiting stronger binding affinity. Light scattering techniques evidenced the formation of polyplexes whose size, molar mass, and surface charge strongly depend on the N/P ratio (nitrogen (N) of the amine group of DMAEMA/QDMAEMA over phosphate (P) groups of DNA), DNA length, and length of the OEGMA chain. Polyplexes presented colloidal stability under physiological ionic strength as shown by dynamic light scattering. In vitro cytotoxicity of the empty nanocarriers was evaluated on HEK293 as a control cell line. P(DMAEMA-co-OEGMA) copolymer aggregates were further assessed for their biocompatibility on 4T1, MDA-MB-231, MCF-7, and T47D breast cancer cell lines presenting high cell viability rates.     

Effect of Zwitterion Substitution on the Structure and Dynamics of Asymmetrically Substituted Polystyrene‐block‐polyisoprene Diblock and Triblock Copolymers

We have studied the effect of zwitterion (Zw) substitution on asymmetrically functionalized copolymers of the type ZwIS, ZwSI (where I is polyisoprene and S is polystyrene), and of diblock and triblock copolymers functionalized at both ends (ZwISZw) and junctions (SZwIZwS), respectively. We have employed SAXS, rheology and dielectric spectroscopy to study the structure and dynamics. The positioning of the short but strongly incompatible polar group with respect to the S and I blocks strongly affects the structure and dynamics of the material because of aggregation. The aggregation strongly modifies the electron density profiles, which reflects in the alteration of the SAXS spectra. The most pronounced effects are found when the functional group is located within the center of the domain with the lowest electron density (polyisoprene).     

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)

BackgroundIn patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.MethodsPatients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).ResultsSymptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.ConclusionsNivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02320058","term_id":"NCT02320058"}}NCT02320058.     

Is the N-of-1 method applicable in bodywork research?Lessons learned using a trial as a methodological pilot

N-of-1 trial designs have rarely been used in bodywork research.Using a recent trial as a methodological pilot,critical issues related to the applicability of N...     

Mixed Hyperbranched/Triblock Copolymer Micelle Assemblies: Physicochemical Properties and Potential for Drug Encapsulation

Mixed micelles have numerous advantages while requiring little to no effort in preparation. This study aims to produce mixed micelle nanostructures from a linear triblock copolymer and a hyperbranched random copolymer, and is able to be loaded with the weakly water-soluble drugs curcumin and indomethacin. Different preparation techniques are employed to produce mixed micelles comprised of Pluronic F127 block copolymer, and hyperbranched poly[(ethylene glycol) methyl ether methacrylate-co-lauryl methacrylate], H-[P(OEGMA-co-LMA)], copolymer. Few studies have dabbled in these types of coassemblies, which provides insight into how structural differences of each copolymer can affect the formation of micelles. To determine the properties of the emerging nanostructures in aqueous environments, including their size, homogeneity, and surface charge, different physicochemical techniques are used, such as light scattering and spectroscopic methods. The results reveal that the copolymers combine, and spontaneously self-assemble into mixed micelle-like nanostructures in aqueous environments, whereas both systems of neat and drug-loaded nanostructures exhibit desirable properties such as small average micelle hydrodynamic radii and low size polydispersity indices. The nanostructures that result from the effective encapsulation of curcumin exhibit outstanding stability over 169 days. The fluorescent qualities of curcumin persist after encapsulation, making the novel nanostructures excellent candidates for bioimaging applications.     

Prospective evaluation of combined local bupivacaine and steroid injections for the management of chronic vaginal and perineal pain

Purpose  

Vaginal/perineal pain is common following obstetric trauma or vaginal surgery for prolapse and may have a serious impact on sexual function and quality of life. Local injections of corticosteroids, local anaesthetic and hyaluronidase are treatment options for chronic pain; however, there are no published studies to support their efficacy. The objective of this study was to evaluate prospectively the efficacy of perineal/vaginal injections for chronic localised pain following childbirth or vaginal surgery.