Clinical pharmacokinetics and pharmacodynamics of topical non-biological therapies for psoriasis patients.

INTRODUCTION: Psoriasis is a chronic inflammatory cutaneous disease that causes patients psychosocial distress. Topical therapies are utilized for mild-to-moderate disease and for more severe disease in conjunction with systemic therapies. Topical corticosteroids are a cornerstone of treatment for psoriasis, but long-term use can cause stria and cutaneous atrophy and as well as systemic side effects such as topical steroid withdrawal. Non-steroidal topical therapies tend to be safer than topical corticosteroids for long-term use. AREAS COVERED: We conducted a literature review on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of topical therapies for psoriasis. We discuss how the PK and PD characteristics of these therapies inform clinicians on efficacy and toxicity when prescribing for patients. EXPERT OPINION: Topical corticosteroids, used intermittently, are very safe and effective. Long-term, continuous use of topical corticosteroids can cause systemic side effects. Several generic and newly approved non-steroidal options are available, but no head-to-head studies compare the effectiveness of the generics (vitamin D analogs, tacrolimus, pimecrolimus) against the newer therapies (roflumilast, tapinarof). Patients often do not respond to topical therapies due to poor adherence to treatment regimens. For patients resistant to topical treatment, phototherapy or systemic therapy may be an option.

Measuring Maxillary Posterior Tooth Movement: A Model Assessment using Palatal and Dental Superimposition.

Since the introduction of Invisalign by Align Technology, Inc. in 1999, questions and debates have persisted regarding the precision of Invisalign (clear aligner) therapy, particularly when compared to the use of traditional fixed appliances. This becomes particularly significant in cases involving anteroposterior, vertical, and transverse corrections, where precise comparisons are of paramount importance. To address these inquiries, this study introduces a meticulously devised protocol, placing a primary emphasis on digitally superimposing the movement of maxillary posterior teeth to facilitate accurate analysis. The sample included 25 patients who had completed their first series of Invisalign (clear) aligners. Four maxillary digital models (pre-treatment, post-treatment, ClinCheck-initial, and final models) were digitally superimposed using the palate rugae and dentitions as stable references. A software combination was used for model superimposition and tooth segmentation. Transformation matrices then expressed the differences between the achieved and predicted tooth positions. Thresholds for clinically relevant differences were at ±0.25 mm for linear displacement and ±2° for rotation. Differences were assessed using Hotelling's T-squared tests with Bonferroni correction. The mean differences in rotation (2.036° ± 4.217°) and torque (-2.913° ± 3.263°) were significant statistically and clinically, with p-values of 0.023 and 0.0003 respectively. De-rotation of premolars and torque control for all posterior teeth were less predictable. All mean differences for the linear measurements were statistically and clinically insignificant, except that the first molars seemed slightly (0.256 mm) more intruded than their predicted position. The clear aligner system appears to meet its prediction for most translational tooth movements and mesial-distal tipping in maxillary posterior teeth for non-extraction cases with mild to moderate malocclusions.

Medical Students' Perceptions and Use of Formal and Informal Curriculum Resources.

Introduction  Resource overload describes the feeling medical students experience in choosing formal (faculty-prescribed) and informal study resources (not faculty-prescribed). This study aims to characterize students' use and perceptions of formal and informal study resources to inform their use in medical education. Methods  This is a mixed-methods study utilizing a convenience sample of first-year medical students enrolled at the University of Central Florida College of Medicine during the academic year 2020-2021. A 40-question, five-point Likert scale, survey based on Keller's Attention, Relevance, Confidence, and Satisfaction (ARCS) Model of Motivational Design was distributed to medical students during the end of their first year of medical school. Multivariate analysis of variance determined differences between formal and informal resources for each construct. Interviews were also conducted by first-year medical students and analyzed using thematic analysis. Learning logs were completed during the beginning of the medical students' second year to assess daily study habits. Results  Fifty-one students completed the survey with a response rate of 42.5%. Informal resources scored higher across all constructs: attention (formal: 3.4±1.2, informal: 4.0±1.1; p<.0125), relevance (formal: 3.8±1.1, informal: 4.3±1.0; p<.0125), confidence (formal: 3.2±1.2, informal: 4.1±1.1; p<.0125), satisfaction (formal: 2.8±1.2, informal: 3.6±1.2; p<.0125) (Likert scale 1-5, Mean±SD). Students found formal resources lacked depth and organization while informal resources allowed for concise understanding with retention cues. Learning log data reported similar use of formal and informal resources during week 1 (88.2% formal vs. 87.8% informal) and week 2 (84.6% formal vs. 82.6% informal). Conclusions  Students preferred informal resources based on ARCS constructs. However, the actual usage of formal and informal resources was similar. Formal resources align more with curricular assessments, but informal resources aid student retention and understanding. Therefore, students find both formal and informal resources necessary for success. Faculty should consider integrating informal curriculum resources to optimize student learning.

Exploration of Patient and Clinician Experience of Video Consultations in Community Palliative Care.

CONTEXT: Telehealth video consultations (VCs) were implemented in the community palliative care team (CPCT) in a regional NSW health district, Australia, as a response to restrictions to the COVID-19 pandemic, using patient's device in the absence of a clinician. OBJECTIVES: To evaluate patient/carer and clinician satisfaction in using VCs for CPC consultations; to explore advantages and challenges of VCs. METHODS: Self-reported online questionnaires to community-dwelling patients under care of the CPCT; seeking patients/carers and clinician perspectives on the VCs from April to September 2020. RESULTS: Of 126 eSurveys completed, (85 clinicians; 41 patients/carers), 97% patient/carers and 97% clinicians indicated they were satisfied with VC. Overall, 93% clinicians agreed they provided same level of care compared to face-to-face review; 85% patients/carers agreed they received same level of care compared to face-to-face consultations and 98% agreed their issues were addressed. Of eSurvey responses 97% clinicians and 78% patients/carers indicated they would continue to use VCs in practice. Comments indicated dissatisfaction with lack of personal examination; some found technological issues to be barriers. Benefits discovered incidentally were empowering patient independence to live out their end-of-life desires while being treated/supported, improved service delivery, increased staff autonomy and upskilling staff. CONCLUSION: Users in this study perceived VCs to have a place in CPC consultations. Using patient device enabled patient freedom, improved timeliness of clinical assessment, and communication to complement face-to-face consults, while minimizing infection risk. Unexpected, but valuable benefits were revealed. Workable technology is paramount.

Rare Autoinflammatory Neutrophilic Dermatoses in Pregnancy: Literature Review.

Rare cases of autoinflammatory neutrophilic dermatoses (AINDs) have been reported in patients during pregnancy with associated adverse maternal and fetal outcomes. Due to the rarity and heterogeneous morphology of pregnancy-associated AINDs, clinical diagnosis is often overlooked, and treatment options are limited. In this review, we present the epidemiology, clinical characteristics, therapeutic interventions, maternal and fetal outcomes, and discuss the possible pathophysiology of various pregnancy associated AINDs. Risk factors for the onset and exacerbation of AINDs in pregnancy include older maternal age, disease duration, and specific gestational age. The varied disease courses and conflicting clinical outcomes in both mothers and fetuses demonstrate the importance of symptom recognition and the understanding of the role of pregnancy on AINDs.

Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the intracellular accumulation of insoluble alpha-synuclein aggregates into Lewy bodies and neurites. Increasing evidence indicates that Parkinson's disease progression results from the spread of pathologic alpha-synuclein through neuronal networks. However, the exact mechanisms underlying the propagation of abnormal proteins in the brain are only partially understood. The objective of this study was first to describe the long-term spatiotemporal distributions of Lewy-related pathology in mice injected with alpha-synuclein preformed fibrils and then to recreate these patterns using a computational model that simulates in silico the spread of pathologic alpha-synuclein. In this study, 87 2-3-month-old non-transgenic mice were injected with alpha-synuclein preformed fibrils to generate a comprehensive post-mortem dataset representing the long-term spatiotemporal distributions of hyperphosphorylated alpha-synuclein, an established marker of Lewy pathology, across the 426 regions of the Allen Mouse Brain Atlas. The mice were injected into either the caudoputamen, nucleus accumbens or hippocampus, and followed over 24 months with pathologic alpha-synuclein quantified at seven intermediate time points. The pathologic patterns observed at each time point in this high-resolution dataset were then compared to those generated using a Susceptible-Infected-Removed (SIR) computational model, an agent-based model that simulates the spread of pathologic alpha-synuclein for every brain region taking simultaneously into account the effect of regional brain connectivity and Snca gene expression. Our histopathological findings showed that differentially targeted seeding of pathological alpha-synuclein resulted in unique propagation patterns over 24 months and that most brain regions were permissive to pathology. We found that the SIR model recreated the observed distributions of pathology over 24 months for each injection site. Null models showed that both Snca gene expression and connectivity had a significant influence on model fit. In sum, our study demonstrates that the combination of normal alpha-synuclein concentration and brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein. We propose that this rich dataset and the related computational model will help test new hypotheses regarding mechanisms that may alter the spread of pathologic alpha-synuclein in the brain.

A Comparative Study of Social Impacts of the COVID-19 Pandemic on Republic of Korea, Japan, and Taiwan.

OBJECTIVE: The frequency of various disasters has become a 21st century global crisis. The biological-disaster of the coronavirus disease of 2019 (COVID-19) gave rise to a multi-dimensional global impact. The 25 items of Societal Influences Survey Questionnaire (SISQ) was developed to assess various categories of social influence during the pandemic. This study compares the SISQ scores of Taiwan, Republic of Korea (Korea) and Japan. METHODS: Persons living in Korea, Japan, and Taiwan were recruited and evaluated through an SISQ online survey. The SISQ is composed of 25 items each with a 4-point Likert scale. The SISQ assesses the following six factors: self-restraint, social impact, government policy, social cost, concern of infection, and awareness of information. A principal factor analysis and reliability (Cronbach's alpha) were performed to validate the SISQ. The analysis of variance (ANOVA) and post-hoc analysis was conducted to explore the differences between groups. RESULTS: The SISQ had acceptable reliabilities, and accounted for 58.86% of the variance. The significance for ANOVA with post-hoc analysis showed that scores of self-restraints ranked highest in Japan followed by Taiwan and Korea. Taiwanese scored lower than other nations regarding the concern of infection. Koreans scored higher in awareness of information than the other two nations. The effect of age and marital status were also estimated. CONCLUSION: The SISQ comprehensively evaluate multiple domains of social influence, and it manifests the divergence of social impacts across the three nations.

The Role of EBV-Encoded LMP1 in the NPC Tumor Microenvironment: From Function to Therapy.

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. It is also characterized by heavy infiltration with non-malignant leucocytes. The EBV-encoded latent membrane protein 1 (LMP1) is believed to play an important role in NPC pathogenesis by virtue of its ability to activate multiple cell signaling pathways which collectively promote cell proliferation and survival, angiogenesis, invasiveness, and aerobic glycolysis. LMP1 also affects cell-cell interactions, antigen presentation, and cytokine and chemokine production. Here, we discuss how LMP1 modulates local immune responses that contribute to the establishment of the NPC tumor microenvironment. We also discuss strategies for targeting the LMP1 protein as a novel therapy for EBV-driven malignancies.

Novel 3D segmentation for reliable volumetric assessment of the nasal airway: a CBCT study.

OBJECTIVE: Nasal airway obstruction affects up to one-third of Americans and is one of the most common complaints by patients to otolaryngologists. Nasal airway obstruction and obstructive sleep apnea syndrome (OSAS) are closely related. The aim of this study was to use the 3D imaging software, ITK-SNAP as a platform to define a gold standard for anatomically accurate boundaries of the nasal airway in 3D CBCT and to create a more reliable and precise 3D CBCT segmentation of the nasal airway for assisting diagnosis, treatment, and monitoring of nasal airway obstruction and OSAS. METHOD AND MATERIALS: After review of the literature to identify established parameters using CBCT and CT technology for the segmentation of the nasal airway, and the existing drawbacks, a gold standard for locating the anatomical boundaries of the nasal airway using CBCT is proposed. This new method aims at standardization of segmentation and quantification, allowing for more reliable comparison between studies. ITK-SNAP software was used to segment three CBCT samples of healthy patients aged 21 to 59 years, who were patients of record, with CBCT obtained for either orthodontic, endodontic, or prosthodontic treatment planning purposes.
Results: The literature search identified 11 studies describing nasal airway parameters utilizing CBCT and CT. A great variation was detected on where the anatomical boundaries for the nasal airway were selected. A new standard in the identification of anatomical boundaries of the nasal airway is proposed for consistent segmentation and quantification using 3D CBCT by using the following landmarks: the inferior ANS-PNS border, the anterior nares border, the posterior sella-PNS border, and superiorly the border in alignment with the base of the skull (excluding the ostia, frontal, ethmoidal, and sphenoidal air cells). The three segmented samples were volumetrically measured, and statistically analyzed. The mean average Hounsfield unit intensity using the CBCT samples in this study was 629 with a standard deviation of 190.
Conclusion: The literature indicates a lack of a gold standard using CBCT technology for the segmentation of the nasal airway. With the proposed standard in this study, it is possible to quantify the nasal airway volume and thereby its reduction. For the general dental practitioner, this is an important aspect during the evaluation of overall airway assessment. This information can be useful in the diagnosis and treatment of airway compromised dental patients. (Quintessence Int 2021;52:154-164; doi: 10.3290/j.qi.a45429).

Evaluation of diagnostic radiology acumen between 2 groups of clinical dental students.

PURPOSE: To evaluate and distinguish if an additional year of clinical experience increases the cognitive ability of dental students to accurately assess and interpret dental radiographs. METHODS: Radiological acuity was assessed between two groups of clinical dental students at Penn Dental Medicine (PDM). Group 1 was composed of 147 third-year dental students (D3), group 2 was composed of 145 fourth-year dental students (D4). A 65-question test comprising the length and breadth of radiographic anatomy and pathology was administered to both D3 and D4 students. The test was designed to test the participants' knowledge of radiographic technique, anatomy, and differential diagnosis. The null hypothesis was that there would be no significant differences between the two groups. RESULTS: STATA 15 software (StataCorp LLC, College Station, TX, USA) was used to statistically analyze the findings. Although, the mean correct score for group 1 was higher (60/65) than group 2 (59/65), there was no statistically significant difference between the performance of the groups. On average, group 1 outperformed the clinically more experienced group 2 on an individual question basis. The average overall number of correctly answered items compared to incorrectly answered items reflected this difference. CONCLUSION(S): An additional year of clinical dental education does not appear to correlate with any higher radiographic acumen. This may be due to tapering exposure to unique pathology and findings, as more routine findings are encountered daily and classroom instruction during the fourth year of dental school is limited. Early incorporation of new radiographic education tools that are clinically oriented may be one method to increase retention of knowledge accumulated in the initial didactic years of dental education.

Development and validation of the Lo's Healthy and Happy Lifestyle Scale (LHHLS): The resilience in general population facing COVID-19 in Taiwan.

BACKGROUND: This article explores the effectiveness of development of the Lo's Healthy and Happy Lifestyle Scale (LHHLS), which is an evaluative tool that monitors the resilience of the Taiwan population in times of such COVID-19 epidemic. Also, to verify factors of resilience, namely the reliability and validity of self-efficacy and positive thinking, and establishment of a prospective norm analysis. METHOD: The study mainly applied Explorative Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) to develop LHHLS and establish the reliability and validity of the tool's structure, verify norm analysis and the reliability of data from each question using Cronbach's alpha. RESULTS: According to statistics, LHHLS has a good factorial effectiveness and relatively high reliability, with factor reliability analyses where Cronbach's alpha lies between 0.83 to 0.94. The 14 questions in the LHHLS has a total variance of 67.04%. The tool includes two sub-assessments that are theoretically and statistically appropriate: mental health/self-efficacy and positive thinking. CONCLUSION: The tool LHHLS can be applied to populations affected by COVID-19. With participants' self-awareness of mental health state and state of happy living, this tool is valid and reliable in assessing and evaluating the resilience of such participants against times of COVID-19. This study can become future use for epidemic prevention communities in monitoring residents' healthy living and changes in their resilience. Also, can become a reference standard for interventions to reduce the impacts populations' happy and healthy living, in times of biological disasters.

Snca-GFP Knock-In Mice Reflect Patterns of Endogenous Expression and Pathological Seeding.

α-Synuclein (aSyn) participates in synaptic vesicle trafficking and synaptic transmission but its misfolding is also strongly implicated in Parkinson's disease (PD) and other neurodegenerative synucleinopathies in which misfolded aSyn accumulates in different regions of the central and peripheral nervous systems. Although increased aSyn expression levels or altered aggregation propensities likely underlie familial PD with SNCA amplification or mutations, the majority of synucleinopathies arise sporadically, indicating that disease can develop under normal levels of wild-type (wt) aSyn. We report here the development and characterization of a mouse line expressing an aSyn-green fluorescence protein (GFP) fusion protein under the control of native Snca regulatory elements. Regional and subcellular localization of the aSyn-GFP fusion protein in brains and peripheral tissues of knock-in (KI) mice are indistinguishable from that of wt littermates. Importantly, similar to wt aSyn, aSyn-GFP disperses from synaptic vesicles on membrane depolarization, indicating that the tag does not alter normal aSyn dynamics at synapses. In addition, intracerebral injection of aSyn pre-formed fibrils into KI mice induced the formation of aSyn-GFP inclusions with a distribution pattern similar to that observed in wt mice, albeit with attenuated kinetics because of the GFP-tag. We anticipate that this new mouse model will facilitate in vitro and in vivo studies requiring in situ detection of endogenous aSyn, thereby providing new insights into aSyn function in health and disease.

The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies.

Epstein-Barr virus (EBV) is closely linked to the development of a number of human cancers. EBV-associated malignancies are characterized by a restricted pattern of viral latent protein expression which is sufficient for the virus to both initiate and sustain cell growth and to protect virus-infected cells from immune attack. Expression of these EBV proteins in malignant cells provides an attractive target for therapeutic intervention. Among the viral proteins expressed in the EBV-associated epithelial malignancies, the protein encoded by the BamHI-A rightward frame 1 (BARF1) is of particular interest. BARF1 is a viral oncoprotein selectively expressed in latently infected epithelial cancers, nasopharyngeal carcinoma (NPC) and EBV-positive gastric cancer (EBV-GC). Here, we review the roles of BARF1 in oncogenesis and immunomodulation. We also discuss potential strategies for targeting the BARF1 protein as a novel therapy for EBV-driven epithelial cancers.

Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy.

Synucleinopathies are composed of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Alpha-synuclein (α-Syn) forms aggregates mainly in neurons in PD and DLB, while oligodendroglial α-Syn aggregates are characteristic of MSA. Recent studies have demonstrated that injections of synthetic α-Syn preformed fibrils (PFFs) into the brains of wild-type (WT) animals induce intraneuronal α-Syn aggregates and the subsequent interneuronal transmission of α-Syn aggregates. However, injections of α-Syn PFFs or even brain lysates of patients with MSA have not been reported to induce oligodendroglial α-Syn aggregates, raising questions about the pathogenesis of oligodendroglial α-Syn aggregates in MSA. Here, we report that WT mice injected with mouse α-Syn (m-α-Syn) PFFs develop neuronal α-Syn pathology after short postinjection (PI) intervals on the scale of weeks, while oligodendroglial α-Syn pathology emerges after longer PI intervals of several months. Abundant oligodendroglial α-Syn pathology in white matter at later time points is reminiscent of MSA. Furthermore, comparison between young and aged mice injected with m-α-Syn PFFs revealed that PI intervals rather than aging correlate with oligodendroglial α-Syn aggregation. These results provide novel insights into the pathological mechanisms of oligodendroglial α-Syn aggregation in MSA.

FGF18, a prominent player in FGF signaling, promotes gastric tumorigenesis through autocrine manner and is negatively regulated by miR-590-5p.

Fibroblast growth factors (FGFs) and their receptors are significant components during fundamental cellular processes. FGF18 plays a distinctive role in modulating the activity of both tumor cells and tumor microenvironment. This study aims to comprehensively investigate the expression and functional role of FGF18 in gastric cancer (GC) and elucidate its regulatory mechanisms. The upregulation of FGF18 was detected in seven out of eleven (63.6%) GC cell lines. In primary GC samples, FGF18 was overexpressed in genomically stable and chromosomal instability subtypes of GC and its overexpression was associated with poor survival. Knocking down FGF18 inhibited tumor formation abilities, induced G1 phase cell cycle arrest and enhanced anti-cancer drug sensitivity. Expression microarray profiling revealed that silencing of FGF18 activated ATM pathway but quenched TGF-ß pathway. The key factors that altered in the related signaling were validated by western blot and immunofluorescence. Meanwhile, treating GC cells with human recombinant FGF18 or FGF18-conditioned medium accelerated tumor growth through activation of ERK-MAPK signaling. FGF18 was further confirmed to be a direct target of tumor suppressor, miR-590-5p. Their expressions showed a negative correlation in primary GC samples and more importantly, re-overexpression of FGF18 partly abolished the tumor-suppressive effect of miR-590-5p. Our study not only identified that FGF18 serves as a novel prognostic marker and a therapeutic target in GC but also enriched the knowledge of FGF-FGFR signaling during gastric tumorigenesis.

Activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. The EBV-encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV-infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1-mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1-mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1-mediated lipogenesis promotes tumor cell growth and is involved in EBV-driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.