Non-viral chimeric antigen receptor (CAR) T cells going viral.

Chimeric antigen receptor (CAR) T cell therapy has made significant strides in the treatment of B-cell malignancies, but its application in treating solid tumors still poses significant challenges. Particularly, the widespread use of viral vectors to deliver CAR transgenes into T cells comes with limitations, including high costs and regulatory restrictions, which hinder the translation of novel genetic engineering concepts into clinical applications. Non-viral methods, such as transposon/transposase and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems, offer promising alternatives for stable transgene insertion in CAR-T cells. These methods offer the potential to increase accessibility and efficiency in the development and delivery of CAR-T cell therapies. The main challenge in using non-viral methods, however, is their low knock-in efficiency, which leads to low transgene expression levels. In this review, we discuss recent developments in non-viral approaches for CAR-T cell production, the manufacturing requirements for clinical-grade production of non-viral CAR-T cells, and the adjustments needed in quality control for proper characterization of genomic features and evaluation of potential genotoxicity.

Patient perspectives of atopic dermatitis: comparative analysis of terminology in social media and scientific literature, identified by a systematic literature review.

Atopic dermatitis (AD) is a chronic skin disease that significantly impacts patient quality of life (QoL). It is unknown whether patients and physicians have the same interpretation of AD burden. Unmet needs and AD disease burden were evaluated by comparing terminology used in social media with terminology used in scientific literature. AD terminology in social media was identified using the NetBase platform, and natural language processing was performed. Topics and words driving negative sentiment were evaluated overall and in relation to specific symptoms. The systematic review of scientific literature identified publications that included AD and QoL terms was identified from PubMed. Term analysis of titles and abstracts was conducted via natural language processing. The occurrence of topics and co-occurrence of words associated with QoL terms were evaluated. More than 3 million social media mentions (2018-2020) and 1519 scientific publications (2000-2020) were evaluated. There were more negative than positive social media mentions, and flare and pain were common symptoms driving negative sentiment. Face and hands were major drivers of negative sentiment in relation to AD symptoms in social media. Sleep and pain were often mentioned together. In scientific literature, pruritus and depression were the most frequently occurring symptoms. Similarly, pruritus was the most common AD symptom co-occurring with QoL terms in the assessed scientific literature. Social media analyses provide a unique view into the patient experience of AD. Symptoms driving negative sentiment in social media appear to be discordantly represented in scientific literature. Incorporating patient perspectives may improve disease understanding and management.

Pregnancy outcomes in patients with psoriasis, psoriatic arthritis, or axial spondyloarthritis receiving ixekizumab.

BACKGROUND: Psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are chronic inflammatory diseases that often affect women of childbearing age. Detailed information about pregnancy and related outcomes across these indications in patients exposed to ixekizumab is lacking. OBJECTIVES: To evaluate pregnancy outcomes after maternal or paternal exposure to ixekizumab in patients with psoriasis, PsA, or axSpA. METHODS: Pregnancy cases from clinical trials and post-marketing reports, associated with either maternal or paternal exposure to ixekizumab cumulatively through 22 March 2019, were identified in the Eli Lilly Global Safety Database and described separately. RESULTS: One hundred and ninety-three ixekizumab-exposed pregnancies were identified. Maternal exposure occurred in 51.3% of pregnancies (clinical trials: n = 58; post-marketing: n = 41). The majority of paternal exposure pregnancies occurred in clinical trials (91 of 94). Live births were reported for 53.8 and 61.1% of known outcomes in maternal exposure pregnancies during clinical trials and post-marketing surveillance, respectively. No congenital malformations resulting from maternal exposure were reported in clinical trials: one case, not causally related to ixekizumab therapy, was recorded in the post-marketing setting. CONCLUSIONS: This integrated safety analysis provides relevant information for clinicians treating patients with psoriasis, PsA, or axSpA with ixekizumab. No new safety signals were identified in patients receiving ixekizumab.

Persistence and clearance of high-risk human papillomavirus and cervical dysplasia at 1 year in women living with human immunodeficiency virus: a prospective cohort study.

OBJECTIVE: Evaluate 1-year outcomes of cervical cancer screening and treatment using primary high-risk human papillomavirus (HPV) testing in women living with human immunodeficiency virus (HIV). DESIGN: Prospective cohort study. SETTING: HIV treatment centre in Botswana. POPULATION: Women living with HIV. METHODS: Participants underwent cervical cancer screening with high-risk HPV testing and triage evaluation at baseline and 1-year follow up. Excisional treatment was offered as indicated. Histopathology was the reference standard. MAIN OUTCOME MEASURES: Persistence, clearance and incidence of high-risk HPV infection; and persistence, progression, regression, cure and incidence of cervical dysplasia. RESULTS: Among 300 women screened at baseline, 237 attended follow up (79%). High-risk HPV positivity significantly decreased from 28% at baseline to 20% at 1 year (P = 0.02). High-risk HPV persistence was 46% and clearance was 54%; incidence was high at 9%. Prevalence of cervical intraepithelial neoplasia Grade 2 (CIN2) or higher was most common in participants with incident high-risk HPV (53%). CIN2 or higher was also common in those with persistent high-risk HPV (32%) and even in those who cleared high-risk HPV (30%). Of the high-risk HPV-positive participants at baseline with

Abnormal liver function tests in acne patients receiving isotretinoin.

BACKGROUND: Isotretinoin is an efficacious treatment option for severe acne. Although isotretinoin often causes mild liver enzyme elevation, how acne patients should be monitored on isotretinoin therapy is not well characterized. OBJECTIVE: The purpose of this study was to assess the management and clinical outcome of acne patients with abnormal aspartate transaminase (AST) and alanine aminotransferase (ALT) when receiving isotretinoin. METHODS: A retrospective chart review was conducted in acne subjects with abnormal AST and ALT levels receiving isotretinoin. Abnormal liver enzymes were graded using the Common Terminology Criteria for Adverse Events version 5. RESULTS: Of 108 subjects with abnormal liver enzymes, 79 subjects were on isotretinoin 80 mg and 23 subjects were on isotretinoin 40 mg. Most abnormalities were during Month 1 of therapy (48). Of the 122 abnormal Grade 1 AST elevations, 40 normalized, 38 remained in Grade 1, and 1 increased into Grade 2 when a healthcare provider maintained the isotretinoin dose. Of the 102 abnormal Grade 1 ALT levels managed by maintaining the isotretinoin dose, 31 normalized and 38 remained persistently elevated. CONCLUSION: Most mild elevations of isotretinoin therapy do not worsen. Acne patients with isotretinoin may not need continued testing when experiencing low-grade liver enzyme abnormalities.

Approaches to training multiclass semantic image segmentation of damage in concrete.

This paper addresses the problem of creating a large quantity of high-quality training segmentation masks from scanning electron microscopy (SEM) images. The images are acquired from concrete samples that exhibit progressive amounts of degradation resulting from alkali-silica reaction (ASR), a leading cause of deterioration, cracking and loss of capacity in much of the nation's infrastructure. The target damage classes in concrete SEM images are defined as paste damage, aggregate damage, air voids and no damage. We approached the SEM segmentation problem by applying convolutional neural network (CNN)-based methods to predict the damage classes due to ASR for each image pixel. The challenges in using the CNN-based methods lie in preparing large numbers of high-quality training labelled images while having limited human resources. To address these challenges, we designed damage- and context-assisted approaches to lower the requirements on human resources. We then evaluated the accuracy of CNN-based segmentation methods using the datasets prepared with these two approaches. LAY DESCRIPTION: This work is about automated segmentation of Scanning Electron Microscopy (SEM) images taken from core and prism samples of concrete. The segmentation must detect several damage classes in each image in order to understand properties of concrete-made structures over time. The segmentation problem is approached with an artificial network (AI) based model. The training data for the AI model are created using damage- and context-assisted approaches to lower the requirements on human resources. The access to all training data and to a web-based validation system for scoring segmented images is available at https://isg.nist.gov/deepzoomweb/data/concreteScoring.

Gentian violet for pyoderma gangrenosum: a retrospective chart review.

Pyoderma gangrenosum is a rare autoinflammatory skin disease. Treatment is multifactorial, addressing inflammation, pain, underlying disease, if present, and the wound. Gentian violet has been used for hundreds of years in a variety of dermatologic conditions for its anti-inflammatory properties. This study aims to evaluate gentian violet in wound healing for pyoderma gangrenosum. We conducted a retrospective chart review of patients with pyoderma gangrenosum treated with gentian violet at the Wake Forest School of Medicine Department of Dermatology in the last 10 years. The primary outcome was clinical improvement. Of the 34 cases that met inclusion criteria, 70% improved with gentian violet, 24% had no documented change, 3% initially improved then worsened, and 3% had unclear results. Gentian violet is a safe and cheap treatment that may improve resolution of pyoderma gangrenosum lesions in addition to systemic therapy.

A changed life: the life experiences of patients with psoriasis receiving biological treatment.

BACKGROUND: Psoriasis has a large negative impact on quality of life and is associated with both depression and anxiety. The introduction of biologics has improved treatment outcomes, but the ways in which patients perceive these improvements are not well characterized. OBJECTIVES: To investigate the everyday life experiences of patients with psoriasis receiving biological treatment in order to gain an understanding of their needs and to improve the quality of care. METHODS: A qualitative narrative methodology was utilized. In total 48 h of participant observations during consultations, and 15 semistructured interviews, were conducted with patients receiving biological treatment. Data were analysed according to Ricoeur's theory of interpretation. RESULTS: Receiving biological treatment was experienced as a turning point, with a significant impact on physical, psychological and emotional levels. However, psychological consequences, such as isolation and social withdrawal, seemed to be a part of the patient's identity; the negative perceptions of psoriasis left marks behind that affected the patient's self-image. Perceived fear of discontinuation of the biological treatment resulted in insecurity, and patients were reluctant to initiate discussion about these concerns with healthcare professionals. CONCLUSIONS: Providing assistance when patients enter the transition of receiving biological treatment may be important. Patients' fear of biological treatment being discontinued is an ongoing issue that healthcare professionals could address.

Patient engagement in clinical guidelines development: input from > 1000 members of the Canadian Osteoporosis Patient Network.

Patient engagement in clinical guidelines development is essential. The results of a self-administered online survey identified themes important to people living with osteoporosis and will inform the development of Osteoporosis Canada clinical guidelines recommendations. INTRODUCTION: Patient engagement is essential in the development of high-quality and relevant guidelines for osteoporosis management. Osteoporosis Canada (OC) is updating its national clinical practice guidelines in collaboration with people living with osteoporosis in the process. METHODS: Using electronic mail, we contacted 6937 members of the Canadian Osteoporosis Patient Network (COPN) to provide input on the selection of relevant content, outcomes, and research questions via a self-administered online survey. Close-ended questions were analyzed using descriptive statistics, and conventional content analysis was conducted for open-ended questions. RESULTS: A total of 1108 individuals completed the survey (97% women, 86% stated they lived with osteoporosis). Most participants considered it critical to have recommendations on physical activity and exercise (74%), fall prevention (69%), nutrition (68%), and initial bone mineral density testing (67%). In addition to preventing fractures, over 75% of respondents stated that consideration of preserving quality of life and ability to perform daily activities, preventing admission to long-term care and fracture-related death, and avoiding serious harms from medications were essential outcomes to consider in evaluating the evidence. In terms of selection of research questions, seven themes emerged from the content analysis including pharmacotherapy, screening and monitoring, diet and supplements, education, exercise, alternative therapies, and pain management. CONCLUSIONS: Patients emphasized that autonomy, mobility, and quality of life are highly valued outcomes and must be integral to practice guideline development. As expected, guidance on pharmacotherapy, screening and monitoring, and fracture prevention were priorities identified to be included in osteoporosis management guidelines.