Association between current cigarette prices and cessation behaviors among male adult smokers: findings from 2018 to 2020 ITC Vietnam surveys.

BACKGROUND: This study evaluated the impact of the tax increase in January 2019 on changes in intention to quit and the effect of cigarette prices on quit attempts and successful quitting among male cigarette smokers in Vietnam. METHODS: Data were derived from the ITC project in Vietnam, which included 1585 adult smokers at baseline (Wave 1, Aug-Oct 2018) followed up to waves 2 (Sep-Nov 2019) and 3 (Sep-Dec 2020). Generalized estimating equations regression was performed to estimate changes in the intention to quit. Multiple logistic regression analysis was used to evaluate the cigarette price of a cigarette pack in relation to quit attempts and successful quitting. RESULTS: The increase in cigarette tax in 2019 did not significantly increase the likelihood of the intention to quit. After the tax increase, 63.6% of participants who smoked made a quit attempt, and 27.6% successfully quit smoking in the follow-up waves. However, the price of a cigarette pack was not significantly associated with quit attempts and successful quitting. The study did not observe a significant impact of cigarette prices on quit attempts and successful quitting in all subgroups of household income. Factors associated with quit attempts included the number of cigarettes smoked and the intention to quit, while those associated with successful quitting included age, dual use of cigarettes and other tobacco products, and the intention to quit. CONCLUSION: Current cigarette prices were not associated with cessation behaviors even within the lowest household income group. Therefore, a sharp rise in cigarette tax is required to incentivize smokers to quit smoking.

Kinetic Barriers to Disproportionation of Salts of Weakly Basic Drugs.

Disproportionation is a major issue in formulations containing salts of weakly basic drugs. Despite considerable interest in risk assessment approaches for disproportionation, the prediction of salt-to-base conversion remains challenging. Recent studies have highlighted several confounding factors other than pHmax that appear to play an important role in salt disproportionation and have suggested that kinetic barriers need to be considered in addition to the thermodynamic driving force when assessing the risk of a salt to undergo conversion to parent free base. Herein, we describe the concurrent application of in situ Raman spectroscopy and pH monitoring to investigate the disproportionation kinetics of three model salts, pioglitazone hydrochloride, sorafenib tosylate, and atazanavir sulfate, in aqueous slurries. We found that even for favorable thermodynamic conditions (i.e., pH ≫ pHmax), disproportionation kinetics of the salts were very different despite each system having a similar pHmax. The importance of free base nucleation kinetics was highlighted by the observation that the disproportionation conversion time in the slurries showed the same trend as the free base nucleation induction time. Pioglitazone hydrochloride, with a free base induction time of <1 min, rapidly converted to the free base in slurry experiments. In contrast, atazanavir sulfate, where the free base induction time was much longer, took several hours to undergo disproportionation in the slurry for pH ≫ pHmax. Additionally, we altered an established thermodynamically based modeling framework to account for kinetic effects (representing the nucleation kinetic barrier) to estimate the solid-state stability of salt formulations. In conclusion, a solution-based thermodynamic model is mechanistically appropriate to predict salt disproportionation in a solid-state formulation, when kinetic barriers are also taken into consideration.

Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers.

Enteric polymers are widely used in amorphous solid dispersion (ASD) formulations. The aim of the current study was to explore ASD failure mechanisms across a wide range of pH conditions that mimic in vivo gastric compartment variations where enteric polymers such as hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are largely insoluble. Delamanid (DLM), a weakly basic drug used to treat tuberculosis, was selected as the model compound. Both DLM free base and the edisylate salt were formulated with HPMCP, while DLM edisylate ASDs were also prepared with different grades of HPMCAS. Two-stage release testing was conducted with the gastric stage pH varied between pH 1.6 and 5.0, prior to transfer to intestinal conditions of pH 6.5. ASD particles were collected following suspension in the gastric compartment and evaluated using X-ray powder diffraction and scanning electron microscopy. Additional samples were also evaluated with polarized light microscopy. In general, ASDs with HPMCP showed improved overall release for all testing conditions, relative to ASDs with HPMCAS. ASDs with the edisylate salt likewise outperformed those with DLM free base. Impaired release for certain formulations at intestinal pH conditions was attributed to surface drug crystallization that initiated during suspension in the gastric compartment where the polymer is insoluble; crystallization appeared more extensive for HPMCAS ASDs. These findings suggest that gastric pH variations should be evaluated for ASD formulations containing weakly basic drugs and enteric polymers.

Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer.

Weakly acid polymers with pH-responsive solubility are being used with increasing frequency in amorphous solid dispersion (ASD) formulations of drugs with low aqueous solubility. However, drug release and crystallization in a pH environment where the polymer is insoluble are not well understood. The aim of the current study was to develop ASD formulations optimized for release and supersaturation longevity of a rapidly crystallizing drug, pretomanid (PTM), and to evaluate a subset of these formulations in vivo. Following screening of several polymers for their ability to inhibit crystallization, hypromellose acetate succinate HF grade (HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro release studies were conducted in simulated fasted- and fed-state media. Drug crystallization in ASDs following exposure to dissolution media was evaluated by powder X-ray diffraction, scanning electron microscopy, and polarized light microscopy. In vivo oral pharmacokinetic evaluation was conducted in male cynomolgus monkeys (n = 4) given 30 mg PTM under both fasted and fed conditions in a crossover design. Three HPMCAS-based ASDs of PTM were selected for fasted-state animal studies based on their in vitro release performance. Enhanced bioavailability was observed for each of these formulations relative to the reference product that contained crystalline drug. The 20% drug loading PTM-HF ASD gave the best performance in the fasted state, with subsequent dosing in the fed state. Interestingly, while food improved drug absorption of the crystalline reference product, the exposure of the ASD formulation was negatively impacted. The failure of the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesized to result from poor release in the reduced pH intestinal environment resulting from the fed state. In vitro experiments confirmed a reduced release rate under lower pH conditions, which was attributed to reduced polymer solubility and an enhanced crystallization tendency of the drug. These findings emphasize the limitations of in vitro assessment of ASD performance using standardized media conditions. Future studies are needed for improved understanding of food effects on ASD release and how this variability can be captured by in vitro testing methodologies for better prediction of in vivo outcomes, in particular for ASDs formulated with enteric polymers.

A Multicenter Study of Clinicopathology and Immunohistochemical Distinction between Adult and Pediatric Large B-Cell Lymphoma.

Introduction: Pediatric DLBCL is considered a homogenous group and has superior outcomes compared to adults. This study investigated the clinical pathology and immunohistochemical distinction between adult and pediatric large B-cell lymphoma. Methods: A cross-sectional study of 314 NHLs with the morphology of diffuse pattern, large B-cell, and CD20 expression was investigated. Results: Of 314 cases, there were 6 cases of pleomorphic MCL (all in adults), 19 cases of Burkitt lymphoma (all in children), and 289 cases of DLBCL. Pediatric DLBCL had many striking differences: More frequency in extra-nodal sites; a higher proportion of centroblastic morphology; a predominance of GCB-type; a high proliferation rate; an infrequency of Bcl2 protein expression, and a lack of double-expresser lymphoma. Conclusions: Our study demonstrated the significant biological differences between adult and pediatric DLBCL.

Phase Behavior and Crystallization Kinetics of a Poorly Water-Soluble Weakly Basic Drug as a Function of Supersaturation and Media Composition.

Understanding the supersaturation and precipitation behavior of poorly water-soluble compounds in vivo and the impact on oral absorption is critical to design consistently performing products with optimized bioavailability. Weakly basic compounds are of particular importance in this context since they have an inherent tendency to undergo supersaturation in vivo upon exit from the stomach and entry into the small intestine because of their pH-dependent solubility. To understand and probe potential in vivo variability of supersaturating systems, rigorous understanding of compound physical properties and phase behavior landscape is essential. Herein, we extensively characterize the solution phase behavior of a model, poorly soluble and weakly basic compound, posaconazole. Phase boundaries for crystal-solution and amorphous-solution were established as a function of pH, allowing possible phase transformations, namely, crystallization or liquid-liquid phase separation, to be mapped for different initial doses and fluid volumes. Endogenous surfactants including sodium taurocholate, lecithin, glycerol monooleate, and sodium oleate in biorelevant media significantly extended the phase boundaries due to solubilization, to an extent that was dependent on the concentration of the surface-active agents. The nucleation induction time of posaconazole was much shorter in biorelevant media in comparison to the corresponding buffer solution, with two distinct regions observed in all media that could be attributed to a change in the nucleation mechanism at high and low supersaturation. The presence of undissolved nanocrystals accelerated the desupersaturation. This work enhances our understanding of biorelevant factors impacting precipitation kinetics, which might affect absorption in vivo. It is expected that findings from this study with posaconazole could be broadly applicable to other weakly basic compounds, after taking into consideration differences in pKa, solubility, and molecular structure.

Perceptions and Use of Electronic Cigarettes Among Young Adults in Vietnam 2020.

Electronic cigarette use among adolescents has increased in the past decade. Little is known about the perception and use of e-cigarettes in Vietnam, especially among young people. This study examines the perceptions and use of electronic cigarettes among young adults in Vietnam. The study uses data from a survey of adult tobacco consumption among adults at the provincial level in 2020, which was funded and managed by the Vietnam Tobacco Control Fund-Ministry of Health. Data were collected from 34 provinces and cities throughout Vietnam and managed using REDCap software. The survey engaged 80,166 participants, of which 9478 were young adults aged 15-24 were selected and reported in this paper. The results show that, at the time of the survey, 2.4% of young Vietnamese adults were smoking e-cigarettes. Many survey participants cited more than one reason for smoking e-cigarettes. These reasons included preferring the taste of e-cigarettes (64.0%), disliking the odour of other cigarettes (46.2%), following the example of family members (44.9%), and believing e-cigarettes threatened fewer health risks (39.1%). Almost half of the e-cigarette users wanted to quit (48%). E-cigarette use was associated with males living in urban areas who are aware of the Law on Prevention and Control of Tobacco Harms. The findings of this study provide evidential data that support public health policies aimed at reducing and ceasing e-cigarette use among young people.

Drug Release and Nanodroplet Formation from Amorphous Solid Dispersions: Insight into the Roles of Drug Physicochemical Properties and Polymer Selection.

Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich nano species (nanodroplets) via liquid-liquid phase separation or glass-liquid phase separation when the drug concentration exceeds the amorphous solubility. These nanodroplets have been shown to be beneficial for ASD performance both in vitro and in vivo. Thus, understanding the generation and stability of nanodroplets from ASD formulations is important. In this study, the impacts of polymer selection and active pharmaceutical ingredient (API) physicochemical properties (wet glass transition temperature (Tg) and log P) on nanodroplet release were studied. Six APIs with different physicochemical properties were formulated as ASDs with two polymers, polyvinylpyrrolidone/vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Their release performance was evaluated using both powder and surface normalized dissolution of compacts. In general, HPMCAS-based dispersions resulted in higher drug release compared to PVPVA-based dispersions. The two polymers also exhibited different trends in nanodroplet formation as a function of drug loading (DL). PVPVA ASDs exhibited a "falling-off-the-cliff" effect, with a dramatic decline in release performance with a small increase in drug loading, while HPMCAS ASDs exhibited a negative "slope" in the release rate as a function of drug loading. For both polymers, low Tg compounds achieved higher levels of nanodroplet formation compared to high Tg compounds. The nanodroplets generated from ASD dissolution were also monitored with dynamic light scattering, and HPMCAS was found to be more effective at stabilizing nanodroplets against size increase. Insights from this study may be used to guide formulation design and selection of excipients based on API physicochemical properties.

Metrology and sensors as dermo-cosmetic technology opportunities for a change of paradigm.

OBJECTIVE: Metrology and measures are changing the way patients and consumers behave and help find new, more effective solutions. METHODS: This Review and Prospective Paper identifies applications in the field of dermatology and beauty tech. RESULTS: The review of skincare as well as dermatological applications and analysis provides a comprehensive picture of the dynamics in the process of impacting the complete value chain in the field of dermo-cosmetics, as well as the opportunities offered by a strict approach around new and innovative measures, especially in the field of better patient/consumer knowledge, understanding, and personalized solution offering. It identifies the new business models or opportunities for the cosmetic industry. CONCLUSION: Adapting metrology and measures to skincare is a significant opportunity to change the way things are done today.

The Sociological Perspective of Users' Invisible Work: A Qualitative Research Framework for Studying Digital Health Innovations Integration.

BACKGROUND: When new technology is integrated into a care pathway, it faces resistance due to the changes it introduces into the existing context. To understand the success or failure of digital health innovations, it is necessary to pay attention to the adjustments that users must perform to make them work, by reshaping the context and sometimes by altering the ways in which they perform activities. This adaptation work, most of which remains invisible, constitutes an important factor in the success of innovations and the ways in which they transform care practices. OBJECTIVE: This work aims to present a sociological framework for studying new health technology uses through a qualitative analysis of the different types of tasks and activities that users, both health professionals and patients, must perform to integrate these technologies and make them work in their daily routine. METHODS: This paper uses a three-part method to structure a theoretical model to study users' invisible work. The first part of the method includes a thematic literature review, previously published by one of the coauthors, of major sociological studies conducted on digital health innovations integration into existing care organizations and practices. The second part extends this review to introduce definitions and applications of the users' invisible work concept. The third part consists of producing a theoretical framework to study the concept according to the different contexts and practices of the users. RESULTS: The paper proposes four dimensions (organizational, interactional, practical, and experiential), each composed of a set of criteria that allow a comparative analysis of different users' work according to different health technologies. CONCLUSIONS: This framework can be applied both as an analytical tool in a research protocol and as an agenda to identify less visible adoption criteria for digital health technologies.

Rapidly and Slowly Growing Lineages in Chromosomal Instability-Type Gland-Forming Gastric Carcinomas as Revealed by Multisampling Analysis of DNA Copy-Number Profile.

BACKGROUND: To examine whether gastric carcinoma (GC) with chromosomal instability (CIN-type GC), the largest category in the Cancer Genome Atlas classification, consists of a single genetic lineage, we conducted a multisampling analysis of genomic DNA copy-number profile. METHODS: We performed array-based comparative genomic hybridization using formalin-fixed paraffin-embedded tissues from 54 gland-forming GCs containing a total of 106 DNA samples from mucosal, extramucosal invasive, and lymph node lesions. Microarray data were analyzed by unsupervised hierarchical clustering and penetrance plots. Epstein-Barr virus infection status and mismatch repair (MMR) enzyme-silencing/p53/mucin expression were examined by in situ hybridization and immunohistochemistry, respectively. RESULTS: The samples examined were divided into gain-rich cluster A and loss-rich cluster B, which were different in tumor locus and patient age. The T1/T2-4 ratio, the frequency of small cancers (diameter ≤2-4 cm), and intestinal mucin expression were higher in cluster B than in cluster A, but there were no significant differences in the frequencies of MMR silencing, mutant p53 pattern, and lymph node metastasis between the 2 clusters. CONCLUSIONS: We demonstrated that CIN-type GC could be categorized into 2 genetic lineages which are different in terms of rapidity of local extension but similar in terms of nodal metastasis risk.

Characterization of the continuous skin fibroblastoid cell line, WE-skin11f, from walleye (Sander vitreus).

A walleye dermal fibroblastoid cell line, WE-skin11f, was established and characterized. WE-skin11f was immunocytochemically positive for two known dermal fibroblast protein markers: vimentin and collagen I. At passage 26, WE-skin11f cultures contained both diploid and aneuploid populations. Ascorbic acid was required to produce extracellular collagen I fibres. Both of the skin fibroblastoid cell lines, WE-skin11f and rainbow trout-derived RTHDF, were not as good as the walleye caudal fin fibroblastoid cell line, WE-cfin11f, at forming abundant dense extracellular collagen matrices. The thermobiology of WE-skin11f was similar to that of other walleye cell lines with 26°C showing best temperature for growth and 4°C showing no growth but 100% viability. The transcript levels of b2m and mhIa genes of the major histocompatibility class I receptor in WE-skin11f were largely similar at all temperatures examined (4, 14, 20 and 26°C). Cortisol had a variety of effects on WE-skin11f cells: growth inhibition, morphological change from fibroblastoid to epithelioid, and enhancement of barrier function. Treatment of WE-skin11f cells with the physiologically relevant concentration of 100 ng/ml cortisol inhibited collagen I synthesis and matrix formation. Thus, WE-skin11f cell line could be useful in fish dermatology, endocrinology, and immunology research.

Severe cutaneous adverse reactions to drugs.

During the past decade, major advances have been made in the accurate diagnosis of severe cutaneous adverse reactions (SCARs) to drugs, management of their manifestations, and identification of their pathogenetic mechanisms and at-risk populations. Early recognition and diagnosis of SCARs are key in the identification of culprit drugs. SCARS are potentially life threatening, and associated with various clinical patterns and morbidity during the acute stage of Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reactions with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. Early drug withdrawal is mandatory in all SCARs. Physicians' knowledge is essential to the improvement of diagnosis and management, and in the limitation and prevention of long-term sequelae. This Seminar provides the tools to help physicians in their clinical approach and investigations of SCARs.

Microstructure of Pharmaceutical Semicrystalline Dispersions: The Significance of Polymer Conformation.

The microstructure of pharmaceutical semicrystalline solid dispersions has attracted extensive attention due to its complexity that might result in the diversity in physical stability, dissolution behavior, and pharmaceutical performance of the systems. Numerous factors have been reported that dictate the microstructure of semicrystalline dispersions. Nevertheless, the importance of the complicated conformation of the polymer has never been elucidated. In this study, we investigate the microstructure of dispersions of polyethylene glycol and active pharmaceutical ingredients by small-angle X-ray scattering and high performance differential scanning calorimetry. Polyethylene glycol with molecular weight of 2000 g/mol (PEG2000) and 6000 g/mol (PEG6000) exhibited remarkable discrepancy in the lamellar periodicity in dispersions with APIs which was attributed to the differences in their folding behavior. The long period of PEG2000 always decreased upon aging-induced exclusion of APIs from the interlamellar region of extended chain crystals whereas the periodicity of PEG6000 may decrease or increase during storage as a consequence of the competition between the drug segregation and the lamellar thickening from nonintegral-folded into integral-folded chain crystals. These processes were in turn significantly influenced by the crystallization tendency of the pharmaceutical compounds, drug-polymer interactions, as well as the dispersion composition and crystallization temperature. This study highlights the significance of the polymer conformation on the microstructure of semicrystalline systems that is critical for the preparation of solid dispersions with consistent and reproducible quality.

Polymorphism of Indomethacin in Semicrystalline Dispersions: Formation, Transformation, and Segregation.

The crystallization of metastable crystal polymorphs in polymer matrices has been extensively reported in literature as a possible approach to enhance the solubility of poorly water-soluble drug compounds, yet no clarification of the mechanism of the polymorph formation has been proposed. The current work aims to elucidate the polymorphism behavior of the model compound indomethacin as well as the mechanism of polymorph selection of drugs in semicrystalline systems. Indomethacin crystallized as either the α- or τ-form, a new metastable form, or a mixture of the two polymorphs in dispersions containing different drug loadings in polyethylene glycol, poloxamer, or Gelucire as the result of the variation in the mobility of drug molecules. As a general rule, low molecular mobility of the amorphous drug favors the crystallization into thermodynamically stable forms whereas metastable crystalline polymorphs are preferred when the molecular mobility of the drug is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients in semicrystalline dispersions and can be used as a guide for polymorphic screening from melt crystallization by tuning the mobility of drug molecules. In addition, the drug crystallized faster while the polymer crystallized slower as the drug-loading increased with the maxima of drug crystallization rate in 70% indomethacin dispersion. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except for when the more stable form was initially dominant. The segregation of τ and α polymorphs as well as the polymorphic transformation during storage led to the inherent inhomogeneity of the semicrystalline dispersions. This study highlights and expands our understanding about the complex crystallization behavior of semicrystalline systems and is crucial for preparation of solid dispersions with reproducible and consistent physicochemical properties and pharmaceutical performance.