Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 2. The biological variability of the murine Local Lymph Node Assay (LLNA) for skin sensitisation

The Local Lymph Node Assay (LLNA) is the most common in vivo regulatory toxicology test for skin sensitisation, quantifying potency as the EC3, the concentration of chemical giving a threefold increase in thymidine uptake in the local lymph node. Existing LLNA data can, along with clinical data, provide useful comparator information on the potency of sensitisers. Understanding of the biological variability of data from LLNA studies is important for those developing non-animal based risk assessment approaches for skin allergy. Here an existing set of 94 EC3 values for 12 chemicals, all tested at least three times in the same vehicle have been analysed by calculating standard deviations (SD) for logEC3 values. The SDs range from 0.08 to 0.22. The overall SD for the 94 logEC3 values is 0.147. Thus the 95% confidence limits (2xSD) for LLNA EC3 values are within a factor of 2, comparable to those for physico-chemical measurements such as partition coefficients and solubility. The residual SDs of Quantitative Mechanistic Models (QMMs) based on physical organic chemistry parameters are similar to the overall SD of the LLNA, indicating that QMMs of this type are unlikely to be bettered for predictive accuracy.     

Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

Effect of hyperdry amniotic membrane in preventing tendon adhesion in a rabbit model

BackgroundNo anti-adhesive materials are currently in clinical use for orthopaedic surgery. We developed a hyperdry amniotic membrane (HD-AM) for easy storage and transplantation as amniotic membrane. The purpose of this study was to examine the application of HD-AM to reduce peritendinous adhesions without impairing tendon healing.MethodsWe randomly divided 3 digits (2nd, 3rd, and 4th digits) from each rabbit into three groups: a tendon repair group; a tendon repair with HD-AM group (HD-AM group); and a control group (cast only). The effects of HD-AM on peritendinous adhesions and tendon healing were examined using microscopic, histological, and mechanical analyses in a rabbit flexor digitorum profundus tendon model.ResultsAdhesions on macroscopic evaluation of the tendon repair site were significantly smaller in the HD-AM group than in the tendon repair group. Little adhesion formation or foreign body reactions were seen by on histologic evaluation in the HD-AM group. Range of motion following tendon repair was significantly better in the HD-AM group than in the tendon repair group. Maximal tensile strength required to pull the tendon from the site of adhesion was significantly smaller in the HD-AM group than in the tendon repair group. As for tendon repair site, no significant difference was seen between the tendon repair and HD-AM groups.ConclusionsHD-AM prevented peritendinous adhesion macroscopically, pathologically, and mechanically without impairing the sutured tendon. HD-AM has already been clinically applied in neurosurgery, ophthalmology, and otolaryngology, and clinical application as an anti-adhesive materials may be achieved in the future.     

Psychometric properties of the Repetitive Behavior Scale-Revised for individuals with autism spectrum disorder in Japan

Restricted and repetitive behaviors (RRBs) constitute a core symptom of autism spectrum disorder (ASD). The Repetitive Behavior Scale-Revised (RBS-R) is a widely used questionnaire administered by parents or caregivers to assess RRBs in individuals with ASD. This study evaluated the psychometric properties of the RBS-R Japanese Version (RBS-R-J). The ASD and non-ASD groups comprised 274 and 36 participants, respectively. We examined corrected item-total correlation, Cronbach's alpha, and RBS-R-J scores of different diagnostic groups, as well as correlations between RBS-R-J scores and intelligence quotient (IQ), autistic symptoms, adaptive/maladaptive functioning, aberrant behaviors, and sensory processing. All items showed moderate corrected item-total correlations. Cronbach's alpha coefficient was .93. We found significant differences in the mean RBS-R-J scores of the low-functioning ASD group and the intellectual disabilities group, and of low-functioning and high-functioning ASD groups. RBS-R-J scores negatively correlated with IQ and scores on the Sensory Profile (Japanese version) and Adaptive Behavior Composite of the Maladaptive Behavior Index of the Vineland Adaptive Behavior Scales-Second Edition (VABS-II; Japanese version), but positively correlated with scores on the peak and current symptoms subscales of the Pervasive Developmental Disorders Autism Society Japan Rating Scale, the VABS-II, and the Aberrant Behavior Checklist-Community (Japanese version). From these results, we conclude that RBS-R-J showed good reliability, diagnostic validity, and convergent validity, indicating that it is a reliable, valid instrument for use among ASD individuals in clinical and research settings.     

Generation and preclinical immunogenicity study of dengue type 2 virus-like particles derived from stably transfected mosquito cells

Recent phase IIb/III trials of a tetravalent live attenuated vaccine candidate revealed a need for improvement in the stimulation of protective immunity against diseases caused by dengue type 2 virus (DENV-2). Our attempts to develop particulate antigens for possibly supplementing live attenuated virus preparation involve generation and purification of recombinant DENV-2 virus-like particles (VLPs) derived from stably (prM+E)-expressing mosquito cells. Two VLP preparations generated with either negligible or enhanced prM cleavage exhibited different proportions of spherical particles and tubular particles of variable lengths. In BALB/c mice, VLPs were moderately immunogenic, requiring adjuvants for the induction of strong virus neutralizing antibody responses. VLPs with enhanced prM cleavage induced higher levels of neutralizing antibody than those without, but the stimulatory activity of both VLPs was similar in the presence of adjuvants. Comparison of EDIII-binding antibodies in mice following two adjuvanted doses of these VLPs revealed subtle differences in the stimulation of anti-EDIII binding antibodies. In cynomolgus macaques, VLPs with enhanced prM cleavage augmented strongly neutralizing antibody and EDIII-binding antibody responses in live attenuated virus-primed recipients, suggesting that these DENV-2 VLPs may be useful as the boosting antigen in prime-boost immunization. As the levels of neutralizing antibody induced in macaques with the prime-boost immunization were comparable to those infected with wild type virus, this virus-prime VLP-boost regimen may provide an immunization platform in which a need for robust neutralizing antibody response in the protection against DENV-2-associated illnesses could be tested.     

Trajectory of adherence to home rehabilitation among older adults with hip fractures and cognitive impairment

This study aimed to identify different trajectories of adherence to home rehabilitation for older adults with hip fracture and cognitive impairment, to examine associations between different adherence trajectories and postoperative recovery outcomes, and to explore the predictors of adherence trajectories. Group-based trajectory modeling showed two adherence trajectories: low (39.06%) and high (60.94%) adherence. The high adherence group had better activities of daily living (β=11.77, p<.001), instrumental activities of daily living (β=0.56, p<.01), femoral muscular strength (β=3.35, p<.01) on the fractured side and quality of life (β=-0.81, p=.02) than the low adherence group. Participants who established exercise habits (OR=6.49, p<.01) and consulted a physical therapist (OR=4.29, p=.03) during hospitalization were more likely to be in the high adherence group.     

The Impact of Job Conditions on Health-Related Quality of Life among Working Japanese Older Adults: A Five-Year Longitudinal Study Using J-MICC Okazaki Study Data

ObjectivesThe number of older adults who continue working after retirement is increasing in Japan. Little is known about how job conditions affect older adults’ health. We examined the association between job conditions and health-related quality of life (HRQOL) during a five-year follow-up study.MethodsThis study included participants aged 65 years or older from the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area recruited at baseline between 2007 and 2011 and followed up five years later. Participants completed a self-reported questionnaire on the physical and mental health aspects of HRQOL (SF-8™), employment status, and job conditions (job satisfaction, skill use, and job suitability).ResultsData of 1,146 men and 522 women were analyzed (mean age: 69.1 and 68.6 years, respectively). Generalized mixed linear regression analysis revealed that, compared to the not-working group, skill use was positively associated with mental health aspects among men (skill use × time: β = 0.16, SE = 0.08, p < 0.05), while poor job satisfaction and job suitability were negatively associated with mental health aspects among women (job satisfaction, not satisfied × time: β = -0.93, SE = 0.47, p < 0.05; job suitability, not suitable × time: β = -1.06, SE = 0.50, p < 0.05).ConclusionsRegarding job conditions among older adults, skill use in men was marginally associated with mental health, and poor job satisfaction and suitability in women were negatively associated with mental health. Considering the job conditions of older workers is necessary to protect their mental health.     

Gender Identity and Non-Binary Presentations in Adolescents Attending Two Specialized Services in Italy

BackgroundRecently, the variability and heterogeneity of gender presentations in transgender youths have gained significant attention worldwide. Alongside this, specialized gender services have reported an increase in referrals of youths reporting non-binary identities. In Italy, studies investigating gender identity and expression in gender non-conforming youths are lacking, as are data regarding the non-binary population.AimThe present study aimed at dimensionally exploring how transgender and non-binary Italian adolescents identify and express their gender.OutcomesGender expression in trans binary youths and non-binary youths.MethodsThe Gender Diversity Questionnaire (GDQ; Twist & de Graaf, 2019) was used to investigate gender identity, gender fluidity, and gender expression in a sample of 125 adolescent patients from the Gender Identity Development Service (SAIFIP) in Rome and the Gender Incongruence Unit of the Careggi Hospital in Florence, between April 2019–June 2021.ResultsThe majority of participants (74.4%) identified as trans* binary and the remaining (25.6%) participants identified as non-binary. Trans binary participants reported a stable gender identity, whereas non-binary participants reported a more fluid gender identity across time and contexts. Almost all participants rated external appearance as important to their gender expression, yet trans binary participants attributed more importance to the body in this respect. Body discomfort and pubertal stage emerged as the most influential factors in participants’ experiences of gender. Participants who were assigned male at birth expressed significantly more desire for puberty blockers, whereas those who were assigned female at birth had a stronger desire to engage in breast/chest surgery. Non-binary participants sought different medical interventions relative to trans binary participants.Clinical ImplicationsThese results may be useful for clinicians working with transgender youths as they provide awareness regarding the features of young people who identify within and outside of binary constructions of gender.Strengths & LimitationsThis study provides useful data in gaining insight into understanding the variety of experiences and challenges of gender non-conforming youths. However as the sample was recruited from specialized services, it may not represent the entire gender non-conforming population in Italy.ConclusionThe results describe the range of gender identities and expressions among gender non-conforming youths attending gender specialized services in Italy, thereby improving our understanding of the variety of identities experienced and the specific medical needs of both trans binary and non-binary adolescents.Mirabella M, Piras I, Fortunato A, et al. Gender Identity and Non-Binary Presentations in Adolescents Attending Two Specialized Services in Italy. J Sex Med 2022;19:1035–1048.     

Is rosacea a systemic disease?

Rosacea is a chronic inflammatory facial disease occurring world-wide. The incidence of rosacea is increasing with age, with the clinical course being characterized by relapses. The pathogenesis of rosacea is not completely understood, but neurovascular and immunologic mechanisms are involved. Rosacea has a number of known extrinsic triggers that should be avoided, such as sun exposure, heat and cold, alcoholic beverages, and spicy food. Of greater importance is the observation that rosacea may develop as a manifestation of systemic diseases with a significant morbidity and even mortality. Obesity, Helicobacter pylori infection, smoking, and inflammatory bowel disease bear a significant risk for the development of rosacea. Metabolic, psychiatric, and neurologic disorders and certain types of cancer show a significant association with rosacea. The possible link to cardiovascular events is debatable. There are extrafacial and extracutaneous manifestations of rosacea, such as the red scalp syndrome, ocular rosacea, and migraine. Rosacea should be considered a systemic disease.