Opportunities of topical drug products in a changing dermatological landscape.

Despite the prevalence and the impact on quality of life of dermatological indications, drug products to treat such conditions have rarely been blockbusters. The prevailing perception of a limited commercial potential of dermatological drug products has restricted innovation and encouraged a more conservative development approach. For example, the focus was on repurposing/reformulation of existing active pharmaceutical ingredients (APIs) specifically for the topical delivery route. However, the situation is quite different today catalyzed in part by the blockbuster success of Dupixent (dupilumab), the first monoclonal antibody treatment for atopic dermatitis which has been approved by the US Food and Drug Administration (US FDA) in 2017. Dupixent's success not only encouraged the development of other biologics but also inspired the (re-)development of new dermal drug products that can reap the many benefits of topical administration. We have also witnessed a shift toward outsourcing development efforts (and associated risks) towards small- to mid-size pharmaceutical companies which often require support of contract research and development/manufacturing organizations (CRO and CDMO). Such trends also emphasize the need of greater expertise in topical formulation design, as well as associated commercial and regulatory considerations. Today, we believe that topical drug products remain not only an essential but also commercially viable class of dermatological therapeutics. In this opinion article, we will address the challenges as well as opportunities of coherent development strategies in the current market environment, formulation innovations of topical drug products and technological advances to facilitate rational topical drug formulation development.

Dual isotope analysis reveals the COVID-19 lockdown impact on nitrate aerosol sources and formation pathways in Shanghai.

Nitrate (NO3-) is an important contributor to PM2.5 which can adversely affect the environment and human health. A noticeable decrease in NOx concentrations has been reported due to the lockdown measures implemented to curb the spread of Corona Virus Disease 2019 (COVID-19). However, questions remain, regarding the nonlinear relationship between NOx and NO3-. Here, we collected PM2.5 samples in two periods, before and during the lockdown of COVID-19 in Shanghai. Dual isotopes (δ18O-NO3- and δ15N-NO3-) of NO3- were measured to investigate the formation pathways and potential sources of NO3-. The results showed that the concentration of NO3- decreased significantly during the lockdown period compared to the period before the lockdown. Additionally, the hydroxyl pathway was the dominant contributor to NO3- production during the lockdown period, while N2O5 hydrolyses dominated the formation of NO3- before the lockdown. This change is largely attributable to alterations in the oxidative potential of the environment. In comparison to the period preceding the lockdown, the relative contributions of each NOx source remained largely unchanged throughout the lockdown periods. Nevertheless, the concentration of NO3- contributed by each NOx source exhibited a notable decline, particularly the mobile sources and coal combustion. Furthermore, the reduction extent of NO3- due to the lockdown period was also greater than the reduction during the Clean Air Actions (2013-2017). Our findings provide evidence that the COVID-19 lockdown led to a decrease in NO3- concentration due to changes in the formation pathway and reductions in NOx emissions from various sources.

Can AI Predict the Magnitude and Direction of Ortho-K Contact Lens Decentration to Limit Induced HOAs and Astigmatism?

Background: The aim is to investigate induced higher-order aberrations (HOA)s and astigmatism as a result of non-toric ortho-k lens decentration and utilise artificial intelligence (AI) to predict its magnitude and direction. Methods: Medmont E300 Video topographer was used to scan 249 corneas before and after ortho-k wear. Custom-built MATLAB codes extracted topography data and determined lens decentration from the boundary and midpoint of the central flattened treatment zone (TZ). An evaluation was carried out by conducting Zernike polynomial fittings via a computer-coded digital signal processing procedure. Finally, an AI-based machine learning neural network algorithm was developed to predict the direction and magnitude of TZ decentration. Results: Analysis of the first 21 Zernike polynomial coefficients indicate that the four low-order and four higher-order aberration terms were changed significantly by ortho-k wear. While baseline astigmatism was not correlated with lens decentration (R = 0.09), post-ortho-k astigmatism was moderately correlated with decentration (R = 0.38) and the difference in astigmatism (R = 0.3). Decentration was classified into three groups: ≤0.50 mm, reduced astigmatism by -0.9 ± 1 D; 0.5~1 mm, increased astigmatism by 0.8 ± 0.1 D; >1 mm, increased astigmatism by 2.7 ± 1.6 D and over 50% of lenses were decentred >0.5 mm. For lenses decentred >1 mm, 29.8% of right and 42.7% of left lenses decentred temporal-inferiorly and 13.7% of right and 9.4% of left lenses decentred temporal-superiorly. AI-based prediction successfully identified the decentration direction with accuracies of 70.2% for right and 71.8% for left lenses and predicted the magnitude of decentration with root-mean-square (RMS) of 0.31 mm and 0.25 mm for right and left eyes, respectively. Conclusions: Ortho-k lens decentration is common when fitting non-toric ortho-k lenses, resulting in induced HOAs and astigmatism, with the magnitude being related to the amount of decentration. AI-based algorithms can effectively predict decentration, potentially allowing for better control over ortho-k fitting and, thus, preferred clinical outcomes.

Corrigendum: Knowledge and thresholds for palliative care and surgery among healthcare providers caring for adults with serious illness.

[This corrects the article DOI: 10.3389/fmed.2024.1351864.].

ASTCT and USCLC Clinical Practice Recommendations for Allogeneic Stem Cell Transplant in Mycosis Fungoides and Sézary Syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease. Sézary syndrome is an aggressive CTCL associated with high morbidity and mortality secondary to immune compromise and opportunistic infection. Although allogeneic hematopoietic cell transplant (allo-HCT) is currently the only available potentially curative treatment modality for MF/SS and is included in NCCN and ASTCT treatment guidelines, there is no published guidance regarding referral criteria, timing and allo-HCT approach to help guide clinicians caring for these patients. Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), non-transplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. Sixteen consensus statements were generated on four topics: (1) criteria for referral for consideration for allo-HCT, (2) allo-HCT preparative regimens and procedures (3) disease status at the time of allo-HCT, and (4) multidisciplinary management in the pre- and post-transplant settings. These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.

Mitigating marine debris: Addressing abandoned, lost, and discarded fishing gears (ALDFGs) in the Sulu-Sulawesi Seas through trilateral cooperation between the Philippines, Indonesia, and Malaysia.

Marine debris substantially threatens the world's marine ecosystems, national economies, and human well-being, particularly those living in the coastal areas. Among the types of marine debris, abandoned, lost, and discarded fishing gears (ALDFGs) are the most challenging, contributing substantially to marine pollution. The Sulu-Sulawesi Seas, a region rich in biodiversity but heavily impacted by fishing activities and ALDFGs, is the focus of this study. In proposing trilateral cooperation between the Philippines, Indonesia, and Malaysia, this paper suggests an eco-regional approach to mitigate its effects. An eco-regional approach looks to balancing ecology and societal needs, integrating environmental conservation and biodiversity with human requirements. The paper explores the effects of ALDFGs on the environment and society, reviews existing national and international laws, and advocates for a trilateral cooperation through eco-regional approach as an effective mitigation method.

A Green Host-Guest Protocol to Improve Water Solubility of Fluorescent Dyes.

Improving fluorescence emission efficiency is essential to develop novel luminescent materials. However, the low water solubility of conventional fluorescent dyes is a serious obstacle to broadening the application scope. Herein, a green protocol have been proposed: Two poorly water-soluble naphthalimide derivatives MONI and MANI with high fluorescent quantum yields (larger than 0.95 in toluene solution) were loaded in three different sizes of cyclodextrin (CD; α, ß, γ-CD) with high water solubility. To further check the feasibility of the proposal, density functional theory (DFT) and time dependent-DFT (TD-DFT) methods combining the Own N-layer Integrated molecular Orbital molecular Mechanics (ONIOM) model with dispersion correction were employed to investigate the geometric and electronic structures of complexes CD·MXNI (X = N, O) in the excited-state process. TD-DFT calculations predict that the fantastic emission behavior of MXNI can be reserved after binding with CD, even improving fluorescent intensity in aqueous solution. Basis set superposition error (BSSE) correction and symmetry adapted perturbation theory (SAPT) were adopted to estimate the complexation energies and weak noncovalent interactions. The middle-sized ß-CD is the perfect candidate to allow fluorescent molecules to settle into its cavity, forming an inclusion complex. Energy decomposition analysis (EDA) indicates that dispersion is superior to electrostatics interaction in embedding-type ß-CD·MXNI, while it is contrary in α,γ-CD·MXNI. NMR calculations further prove the existence of a strong intermolecular hydrogen bond interaction between host and guest. Weak interactions that limited molecular vibration and hampered the nonradiative inactivation channel are conducive to the enhanced emission intensity.

Distinct functional diversity of branched oligosaccharides as chaperones and inhibitory-binding partners of amyloid beta-protein and its aggregates.

Aggregation and deposition of amyloid beta-protein 1-42 (Aß42) in the brain, primarily owing to hydrophobic interactions between Aß42 chains, is a common pathology in all forms of Alzheimer's disease (AD). Hydrophilic oligosaccharides are widely present in the extracellular matrix and on the cytoplasmic membrane. To determine if oligosaccharides bind to Aß42 or its aggregates and consequently affect their aggregation and cellular function, this study examined the interaction of typical functional oligosaccharides with Aß42 or its aggregates. Isomaltooligosaccharides (IMOs), particularly isomaltotriose, panose, and isomaltotetraose, functioned as molecular chaperones for Aß42 by binding directly to Aß42, preserving Aß42's active conformation and cytotrophic activity. Oral IMOs reduced total plasma Aß level and indirectly caused a slight reduction in the load of Aß42 spots/plaques in the brain of AD model mice (male). Another branched oligosaccharide, bianntennary core pentasaccharide (BCP), had a relatively high binding specificity for Aß42 oligomers (Aß42O) and acted as an antagonistic binding partner for Aß42O. Free BCP effectively blocked/prevented further assembly of Aß42O and their toxicity to neural and vascular endothelial cell lines. Since BCP is also a signaling component of membrane targets (glycolipids, glycoproteins or receptors), it seemed that BCP had two opposing effects on the binding of Aß42O to target cells. This study's findings suggest that these branched oligosaccharides may be potential candidates for blocking or preventing Aß42 aggregation and Aß42O cytotoxicity/neurotoxicity, respectively, and that IMO-like or free BCP-like oligosaccharide deficiencies in the brain may be one of the underlying mechanisms for Aß42 aggregation and Aß42O cytotoxicity.

Photoinduced Nonadiabatic Dynamics of a Single-Walled Carbon Nanotube-Porphyrin Complex.

Single-walled carbon nanotubes (SWCNTs) have gained a lot of attention in the past few decades due to their promising optoelectronic properties. In addition, SWCNTs can form complexes that have good chemical stability and transport properties with other optical functional materials through noncovalent interactions. Elucidating the detailed mechanism of these complexes is of great significance for improving their optoelectronic properties. Nevertheless, simulating the photoinduced dynamics of these complexes accurately is rather challenging since they usually contain hundreds of atoms. To save computational efforts, most of the previous works have ignored the excitonic effects by employing nonadiabatic carrier (electron and hole) dynamics simulations. To properly consider the influence of excitonic effects on the photoinduced ultrafast processes of the SWCNT-tetraphenyl porphyrin (H2TPP) complex and to further improve the computational efficiency, we developed the nonadiabatic molecular dynamics (NAMD) method based on the extended tight binding-based simplified Tamm-Dancoff approximation (sTDA-xTB), which is applied to study the ultrafast photoinduced dynamics of the noncovalent SWCNT-porphyrin complex. In combination with statically electronic structure calculations, the present work successfully reveals the detailed microscopic mechanism of the ultrafast excitation energy transfer process of the complex. Upon local excitation on the H2TPP molecule, an ultrafast energy transfer process occurs from H2TPP (SWCNT-H2TPP*) to SWCNT (SWCNT*-H2TPP) within 10 fs. Then, two slower processes corresponding to the energy transfer from H2TPP to SWCNT and hole transfer from H2TPP to SWCNT take place in the 1 ps time scale. The sTDA-xTB-based electronic structure calculation and NAMD simulation results not only match the previous experimental observations from static and transient spectra but also provide more insights into the detailed information on the complex's photoinduced dynamics. Therefore, the sTDA-xTB-based NAMD method is a powerful theoretical tool for studying the ultrafast photoinduced dynamics in large extended systems with a large number of electronically excited states, which could be helpful for the subsequent design of SWCNT-based functional materials.

Effect of Deformation Mode on Grain Characteristics and Strength-Toughness of Al-Zn-Mg-Cu Alloy.

The Al-Zn-Mg-Cu alloy plate is a structural material widely used in aerospace, and its rolling process plays a crucial role in determining its performance. This study investigated the effects of different pass combinations of forward and spread rolling on the grain characteristics, strength, and fracture toughness of Al-Zn-Mg-Cu aluminum alloy plates under industrial conditions. The results show that initially using a small pass reduction followed by a larger one can improve the grain width and thickness on the Long Transverse-Short Transverse surface. Additionally, increasing the spread rolling pass enhances the grain width-to-thickness ratio on the TS surface. Performance tests indicate that grain characteristics have minimal influence on room-temperature tensile properties. However, a higher grain width-to-thickness ratio significantly improves the alloy's fracture toughness.