Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report ...the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.
The hypothesis of a functional disconnection of neuro-cognitive networks in patients with mild cognitive impairment (MCI) and Alzheimer Dementia was investigated using baseline resting EEG data. EEG ...databases from New York (264 subjects) and Stockholm (155 subjects), including healthy controls and patients with varying degrees of cognitive decline or Alzheimer Dementia were analyzed using Global Field Synchronization (GFS), a novel measure of global EEG synchronization. GFS reflects the global amount of phase-locked activity at a given frequency by a single number; it is independent of the recording reference and of implicit source models. Patients showed decreased GFS values in Alpha, Beta, and Gamma frequency bands, and increased GFS values in the Delta band, confirming the hypothesized disconnection syndrome. The results are discussed within the framework of current knowledge about the functional significance of the affected frequency bands.
We present a plasmon-active hybrid nanomaterial design with electrochemical tunability of the localized surface plasmon resonances. The plasmonic-active nanostructures are composed of silver nanocube ...aggregates embedded into an electrochromic polymer coating on an indium tin oxide electrode with the nanocube aggregation controlled by the surface pressure. Such polymer–nanocube hybrid nanomaterials demonstrated unique tunable plasmonic behavior under an applied electrochemical potential. A significant reversible experimental peak shift of 22 nm at an electrical potential of 200 mV has been achieved in these measurements. Finite-difference time-domain (FDTD) simulations show that, under full oxidation potential, a maximal spectral shift of ca. 80 nm can be potentially achieved, which corresponds to a high sensitivity of 178 nm per refractive index unit. Furthermore, FDTD modeling suggests that the electrochemically controlled tunability of plasmonic peaks is caused by reversible changes in the refractive index of the electrochromic polymer coating caused by oxidation or reduction reactions under external electrical potential. Consequently, we define the orthogonal plasmonic resonance shift as a shift that is orthogonal to the redox process responsible for the refractive index change. On the basis of these results, we suggest that the combination of anisotropic nanostructures and electrochromic matrix has the potential to reversibly electrically tune plasmonic resonances over the full visible spectrum.
We examine how to sensibly integrate spirituality into the care of older adult medical and psychiatric patients from a multi-cultural perspective. First, definitions of spirituality and spiritual ...integration are provided. Second, we examine the logic that justifies spiritual integration, including research that demonstrates an association between religious/spiritual (R/S) involvement and health in older adults and research that indicates widespread spiritual needs in later life and the consequences of addressing or ignoring them. Third, we describe how and when to integrate spirituality into the care of older adults, i.e. taking a spiritual history to identify spiritual needs and then mobilizing resources to meet those needs. Fourth, we examine the consequences of integrating spirituality on the well-being of patients and on the doctor–patient relationship. Finally, we describe boundaries in addressing R/S issues that clinicians should be cautious about violating. Resources will be provided to assist with all of the above.
The quantum spin Hall (QSH) state is a state of matter characterized by a non-trivial topology of its band structure, and associated conducting edge channels. The QSH state was predicted and ...experimentally demonstrated to be realized in HgTe quantum wells. The existence of the edge channels has been inferred from local and non-local transport measurements in sufficiently small devices. Here we directly confirm the existence of the edge channels by imaging the magnetic fields produced by current flowing in large Hall bars made from HgTe quantum wells. These images distinguish between current that passes through each edge and the bulk. On tuning the bulk conductivity by gating or raising the temperature, we observe a regime in which the edge channels clearly coexist with the conducting bulk, providing input to the question of how ballistic transport may be limited in the edge channels. Our results represent a versatile method for characterization of new QSH materials systems.
The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation ...in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary ...resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
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•SHH-MBs in infants, children, and adults are genomically distinct from each other•Most adult, but only half of the pediatric, SHH-MBs will respond to SMO inhibition•Tumor predisposition (PTCH1, SUFU, TP53) is highly prevalent in pediatric SHH-MB•Recurrent mutations outside the SHH-pathway suggest rational combination therapies
Smoothened (SMO) inhibitors are in clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB), but response varies. By profiling a large SHH-MB cohort, Kool et al. reveal age-dependent genomic distinction and demonstrate genotype-related response to SMO inhibition using patient-derived xenograft cells.
Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane ...conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure–activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.
The liver is the most common organ injured in blunt abdominal trauma and makes up roughly 5% of all trauma admissions. Current treatments are invasive and resource-intensive, which may delay care. We ...aim to develop and validate a contrast-enhanced ultrasound (CEUS)guided noninvasive tool to treat liver lacerations at the bedside.
Two 1.8 MHz high-intensity focused ultrasound (HIFU) elements were coupled to a C1-6 diagnostic ultrasound probe and a Logiq E10 scanner (GE HealthCare) utilizing a custom enclosure for co-registered imaging and ablation. A phantom was created from polyacrylamide gel combined with thermochromic ink whose color changes above biological ablative temperatures (60 °C). The HIFU wave was focused approximately 0.5 cm below the surface utilizing a 50% duty cycle generating 11.9 MPa for 20, 30, 40, 50, and 60s. Experiments were repeated on ex vivo chicken livers in a water bath. Finally, the livers of 4 live swine underwent up to 6 CEUS-guided treatments using parameters optimized from in vitro work.
Treatment of the phantom between 20-60s, produced ablation sizes from 0.016 to 0.4 cm 3 . The relationship between time and size was exponential (R 2 = 0.992). Ablation areas were also well visualized on with ultrasound imaging. The ex vivo liver ablation size at 20s was 0.37 cm 3 , at 30s was 0.66 cm 3 , and at 100 s was 5.0 cm 3 . For the in-vivo swine experiments, the average ablation area measured 2.0x0.75 cm with a maximum of 3.5x1.5 cm. CEUS was utilized with the contrast agent Definity (Lantheus) for identification of lacerations as well as immediate post operative evaluation of therapy.
These experiments demonstrate the feasibility of CEUS guided transdermal HIFU ablation and the time-dependent size of ablation. This work warrants future investigations into using ultrasound to detect active bleeding and HIFU to coagulate grade III and IV liver laceration.
Therapeutic/care management.
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