Long-term effects of volanesorsen on triglycerides and pancreatitis in patients with familial chylomicronaemia syndrome (FCS) in the UK Early Access to Medicines Scheme (EAMS).

BACKGROUND AND AIMS: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies. METHODS: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks. RESULTS: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 109/L. CONCLUSIONS: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure.

Low Cost and Easy Validation Anticounterfeiting Plasmonic Tags Based on Thin Films of Metal and Dielectric.

Multilevel anticounterfeiting Physical Unclonable Function (PUF) tags based on thin film of silver (Ag), Zinc Oxide (ZnO) and PolyVinylPyrrolidone (PVP), are experimentally demonstrated and validated. We exploit the low adhesion of silver to glass and consequent degradation during ZnO deposition to induce morphological randomness. Several photographs of the tag surfaces have been collected with different illumination conditions and using two smartphones of diverse brand. The photos were analyzed using an image recognition algorithm revealing low common minutiae for different tags. Moreover, the optical response reveals peculiar spectra due to labels of plasmonic nature. The proposed systems can be easily fabricated on large areas and represent a cost-effective solution for practical protection of objects.

The Many Fictions of Illness: A Rhetorical Approach to Understanding Fictionality in Mom's Cancer.

Recent studies of fictionality within narrative theory have emphasized the permeability between global fictions and nonfictions. That is, global nonfictions often deploy elements of local fictionality without compromising their global commitments. This paper seeks to contribute to this ongoing exploration by arguing that nonfictional illness narratives deploy fictionality to enrich their referential content. I examine Brian Fies' graphic memoir Mom's Cancer, emphasizing how the text utilizes fictionality to address the complicated question of how to narrate the illness experience of others. I also move beyond the particulars of Mom's Cancer to consider (a) how the graphic medium lends itself to the inventions of fictionality, (b) why authors of illness narrative often turn to the indirections of fictionality to come to terms with the actual experiences of illness, and c) how a rhetorical understanding of fictionality can help answer recent challenges to the role of narrative studies in the medical humanities.

Atherosclerosis in Fabry Disease-A Contemporary Review.

Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.

Acute Confusion as an Initial Presentation of SARS-CoV-2 Infection.

BACKGROUND AND PURPOSE: The respiratory manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been extensively documented. There is emerging evidence that coronavirus disease 2019 (COVID-19) has number of other presenting features which might not be related to the severity of the respiratory disease. We have previously described a case of hypoactive delirium as the first manifestation of COVID-19 without profound lung disease. Here we present five cases of elderly patients, without a prior history of dementia and had no overt COVID-19-related pneumonia, who presented with the acute onset of delirium as the primary manifestation of COVID-19. METHODS: This retrospective, single-center study performed a health informatics search to produce a list of patients who were admitted with acute confusion and tested positive for the SARS-CoV-2 virus between March 1 and June 30, 2020. The electronic medical admission notes were screened for all patients with confusion who tested positive for SARS-CoV-2. Patients with a history of dementia and a high risk of delirium were excluded, such as severe COVID-19-related pneumonia or any other infection, malignancy, drugs, or severe illness of any kind. RESULTS: During the first wave of the COVID-19 pandemic our hospital experienced just over 3,000 SARS-CoV-2 positive patients, and 45 of them had documented confusion upon admission. Secondary causes for their acute confusion were excluded. Five patients were identified as having delirium as the initial presentation of COVID-19-related illness without significant COVID-19-related pneumonitis. None of them had overt chest symptoms or a previous history of confusion, and the 3 patients who underwent head CT scans had normal findings. CONCLUSIONS: This case series illustrates the importance of recognizing acute confusion as the first manifestation of COVID-19 in susceptible individuals.

Leveraging on ENZ Metamaterials to Achieve 2D and 3D Hyper-Resolution in Two-Photon Direct Laser Writing.

A novel technique is developed to improve the resolution of two-photon direct laser writing lithography. Thanks to the high collimation enabled by extraordinary εNZ (near-zero) metamaterial features, ultrathin dielectric hyper-resolute nanostructures are within reach. With respect to the standard direct laser writing approach, a size reduction of 89% and 50%, in height and width respectively, is achieved with the height of the structures adjustable between 5 and 50 nm. The retrieved 2D fabrication parameters are exploited for realizing extremely thin all-dielectric metalenses tailored through deep machine learning codes. The hyper-resolution achieved in the writing process enables the fabrication of a highly detailed dielectric 3D bas-relief (with full height of 500 nm) of Da Vinci's "Lady with an Ermine". The proof-of-concept results show intriguing cues for the current and trendsetting research scenario in anti-counterfeiting applications and ultracompact photonics, paving the way for the realization of all-dielectric and apochromatic ultrathin imaging systems.

A case series of cerebral venous thrombosis as the first manifestation of homocystinuria.

Background: Cerebral venous thrombosis (CVT) is an important cause of stroke particularly in younger patients and potentially fatal if diagnosis is delayed. The presentation of symptoms is highly variable and consequently the diagnosis and underlying cause is often delayed or overlooked. Homocystinuria, a rare autosomal recessive disorder is an identified risk factor for CVT. Purpose: A timely diagnosis and treatment of the underlying cause of CVT could result in improved outcome and prevent further events. This case series describes the clinical course of six adults presented with unprovoked CVT, in whom the diagnosis of underlying homocystinuria was delayed with adverse consequences. We aim to highlight the importance of recognising homocystinuria as an underlying cause of CVT and offer a practical approach to the diagnosis and management. Methods: This is a retrospective case series of a cohort of 30 consecutive patients seen in a UK tertiary referral centre. Result: Six out of 30 patients presented with CVT prior to homocystinuria diagnosis. The mean and range of age at the time of the first CVT episode was 22.6 (range 11-31) years. The mean ±SD age at diagnosis of homocystinuria as the underlying cause was 26 ± 4.2 years. The time between first CVT and diagnosis of homocystinuria ranged from 1.6 to 11 years resulting in a delay to introduction of effective treatment and, in some cases, a further large vessels thrombotic event. Conclusion: Physician awareness of homocystinuria as an underlying cause for an unprovoked CVT will facilitate timely introduction of effective treatment to prevent a further event.

Investigation of tryptophan-related yellowing in parenteral amino acid solution: Development of a stability-indicating method and assessment of degradation products in pharmaceutical formulations.

Parenteral amino acid solutions containing tryptophan tend to develop a yellow colouration upon storage. Hence, the aim of the present study was to find out whether tryptophan degradation products are the reason for the yellowing. The degree of discolouration and tryptophan degradation was examined by visual examination and UV/Vis measurements with respect to oxygen presence, pH value, and duration of steam sterilization. LC-UV analyses of autoclaved tryptophan solutions indicated eight degradation products, namely R,R/R,S 2-amino-3-(oxoindolin-3-yl)propanoic acid, R,R/R,S 2-amino-3-hydroxy-2-oxoindolin-3-yl)propanoic acids, cis/trans 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid, N´-formylkynurenine, and kynurenine. The proposed degradation products were confirmed by spiking of synthesized degradation products and LC-UV/MS analyses. The LC-UV analysis method was optimized and validated according to the ICH guideline Q2 (R1). Tryptophan stability in commercially available parenteral amino acid formulations was evaluated over a storing period of 12 months in two common types of primary packaging after autoclave procedure.

Toroidal metasurface resonances in microwave waveguides.

We theoretically investigate the possibility to load microwave waveguides with dielectric particle arrays that emulate the properties of infinite, two-dimensional, all-dielectric metasurfaces. First, we study the scattering properties and the electric and magnetic multipole modes of dielectric cuboids and identify the conditions for the excitation of the so-called anapole state. Based on the obtained results, we design metasurfaces composed of a square lattice of dielectric cuboids, which exhibit strong toroidal resonances. Then, three standard microwave waveguide types, namely parallel-plate waveguides, rectangular waveguides, and microstrip lines, loaded with dielectric cuboids are designed, in such a way that they exhibit the same resonant features as the equivalent dielectric metasurface. The analysis shows that parallel-plate and rectangular waveguides can almost perfectly reproduce the metasurface properties at the resonant frequency. The main attributes of such resonances are also observed in the case of a standard impedance-matched microstrip line, which is loaded with only a small number of dielectric particles. The results demonstrate the potential for a novel paradigm in the design of "metasurface-loaded" microwave waveguides, either as functional elements in microwave circuitry, or as a platform for the experimental study of the properties of dielectric metasurfaces.

Anapole Modes in Hollow Nanocuboid Dielectric Metasurfaces for Refractometric Sensing.

This work proposes the use of the refractive index sensitivity of non-radiating anapole modes of high-refractive-index nanoparticles arranged in planar metasurfaces as a novel sensing principle. The spectral position of anapole modes excited in hollow silicon nanocuboids is first investigated as a function of the nanocuboid geometry. Then, nanostructured metasurfaces of periodic arrays of nanocuboids on a glass substrate are designed. The metasurface parameters are properly selected such that a resonance with ultrahigh Q-factor, above one million, is excited at the target infrared wavelength of 1.55 µm. The anapole-induced resonant wavelength depends on the refractive index of the analyte superstratum, exhibiting a sensitivity of up to 180 nm/RIU. Such values, combined with the ultrahigh Q-factor, allow for refractometric sensing with very low detection limits in a broad range of refractive indices. Besides the sensing applications, the proposed device can also open new venues in other research fields, such as non-linear optics, optical switches, and optical communications.

Guided-mode resonant narrowband terahertz filtering by periodic metallic stripe and patch arrays on cyclo-olefin substrates.

We experimentally and theoretically demonstrate a class of narrowband transmissive filters in the terahertz spectrum. Their operation is based on the excitation of guided-mode resonances in thin films of the low-loss cyclo-olefin polymer Zeonor, upon which aluminum stripe and patch arrays are patterned via standard photolithography. The filters are engineered to operate in low atmospheric loss THz spectral windows, they exhibit very high transmittance and quality factors, compact thickness, and mechanical stability. The dependence of their filtering properties on the geometrical parameters, the substrate thickness and the angle of incidence is investigated, discussing the physical limitations in their performance. This class of filters provides a cost-effective solution for broadband source or channel filtering in view of emerging terahertz wireless communication systems.

Directional Emission of Fluorescent Dye-Doped Dielectric Nanogratings for Lighting Applications.

By structuring a luminescent dielectric interface as a relief diffraction grating with nanoscale features, it is possible to control the intensity and direction of the emitted light. The composite structure of the grating is based on a fluorescent dye (Lumogen F RED 305) dispersed in a polymeric matrix (poly(methyl methacrylate)). Measurements demonstrate a significant enhancement of the emitted light for specific directions and wavelengths when the grating interface is compared to nonstructured thin films made of the same material. In particular, the maximum enhancement of photoluminescence for a given pump wavelength is obtained at an angle of incidence that is close to the Rayleigh anomaly condition for the first-order diffracted waves. In this condition, the maximum extinction of incident light is observed. Upon excitation with coherent and monochromatic sources, photoluminescence plots show that the Rayleigh anomalies confine the angular interval of the emitted light. Being the anomalies  directly related to the pitch of the diffraction grating, the system can be thus implemented as an optical device whose directional emission can be designed for specific applications. The exploitation of nanoimprinting techniques for the fabrication of the luminescent grating enables production of the device on large areas, paving the way for low-cost lighting and solar applications.

A diversity oriented synthesis of natural product inspired molecular libraries.

Natural products are the source of innumerable pharmaceutical drug candidates and also form an important aspect of herbal remedies. They are also a source of various bioactive compounds. Herein we have leveraged the structural attributes of several natural products in building a library of architecturally diverse chiral molecules by harnessing R-tryptophan as the chiral auxiliary. It is converted to its corresponding methyl ester 1 which in turn provided a bevy of 1-aryl-tetrahydro-ß-carbolines 2a-d, which were then converted to chiral compounds via a diversity oriented synthetic strategy (DOS). In general, intermolecular and intramolecular ring rearrangements facilitated the formation of the final compounds. Four different classes of molecules with distinct architectures were generated, adding up to nearly twenty-two individual molecules. Phenotypic screening of a representative section of the library revealed two molecules that selectively inhibit MCF7 breast cancer cells with IC50 of ∼5 µg mL-1 potency.