Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Psoriasis is a chronic disease that requires long‐term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)‐23. This article reviews published data on the safety of these IL‐23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo‐ and active‐controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk–benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL‐23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL‐23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long‐term extension studies and patient registries will further establish the safety profile of IL‐23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.     

A process evaluation of implementing a vocational enablement protocol for employees with hearing difficulties in clinical practice

Objective: A multidisciplinary vocational rehabilitation programme, the Vocational Enablement Protocol (VEP) was developed to address the specific needs of employees with hearing difficulties. In the current study we evaluated the process of implementing the VEP in audiologic care among employees with hearing impairment. Design: In conjunction with a randomized controlled trial, we collected and analysed data on seven process parameters: recruitment, reach, fidelity, dose delivered, dose received and implemented, satisfaction, and perceived benefit. Study sample: Sixty-six employees with hearing impairment participated in the VEP. The multidisciplinary team providing the VEP comprised six professionals. Results: The professionals performed the VEP according to the protocol. Of the recommendations delivered by the professionals, 31% were perceived as implemented by the employees. Compliance rate was highest for hearing-aid uptake (51%). Both employees and professionals were highly satisfied with the VEP. Participants rated good perceived benefit from it. Conclusions: Our results indicate that the VEP could be a useful treatment for employees with hearing difficulties from a process evaluation perspective. Implementation research in the audiological setting should be encouraged in order to further provide insight into parameters facilitating or hindering successful implementation of an intervention and to improve its quality and efficacy.     

Novel phenotype of mouse spermatozoa following deletion of nine β-defensin genes

β-defensin peptides are a large family of antimicrobial peptides. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. Despite their inducible presence at mucosal surfaces, their main site of expression is the epididymis. Recent evidence suggests that a major function of these peptides is in sperm maturation. In addition to previous work suggesting this, work at the MRC Human Genetics Unit, Edinburgh, has shown that homozygous deletion of a cluster of nine β-defensin genes in the mouse results in profound male sterility. The spermatozoa derived from the mutants had reduced motility and increased fragility. Epididymal spermatozoa isolated from the cauda region of the homozygous mutants demonstrated precocious capacitation and increased spontaneous acrosome reactions compared with those from wild-types. Despite this, these mutant spermatozoa had reduced ability to bind to the zona pellucida of oocytes. Ultrastructural examination revealed a disintegration of the microtubule structure of mutant-derived spermatozoa isolated from the epididymal cauda region, but not from the caput. Consistent with premature acrosome reaction and hyperactivation, spermatozoa from mutant animals had significantly increased intracellular calcium content. This work demonstrates that in vivo β-defensins are essential for successful sperm maturation, and that their disruption alters intracellular calcium levels, which most likely leads to premature activation and spontaneous acrosome reactions that result in hyperactivation and loss of microtubule structure of the axoneme. Determining which of the nine genes are responsible for the phenotype and the relevance to human sperm function is important for future work on male infertility.     

Interpersonal Counseling in the Treatment of Adolescent Depression: A Randomized Controlled Effectiveness and Feasibility Study in School Health and Welfare Services

In order to offer early and accessible treatment for adolescents with depression, brief and effective treatments in adolescents’ everyday surroundings are needed. This randomized controlled trial studied the preliminary effectiveness, feasibility, and acceptability of interpersonal counseling (IPC) and brief psychosocial support (BPS) in school health and welfare services. The study was conducted in the 28 lower secondary schools of a large city in Southern Finland, randomized to provide either IPC or BPS. Help-seeking 12–16-year-old adolescents with mild-to-moderate depression, with and without comorbid anxiety, were included in the study. Fifty-five adolescents received either 6 weekly sessions of IPC or BPS and two follow-up sessions. Outcome measures included self- and clinician-rated measures of depression, global functioning, and psychological distress/well-being. To assess feasibility and acceptability of the treatments, adolescents’ and counselors’ treatment compliance and satisfaction with treatment were assessed. Both treatments were effective in reducing depressive disorders and improving adolescents’ overall functioning and well-being. At post-treatment, in both groups, over 50% of adolescents achieved recovery based on self-report and over 70% based on observer report. Effect sizes for change were medium or large in both groups at post-treatment and increased at 6-month follow-up. A trend indicating greater baseline symptom severity among adolescents treated in the IPC-providing schools was observed. Adolescents and counselors in both groups were satisfied with the treatment, and 89% of the adolescents completed the treatments and follow-ups. This trial suggests that both IPC and BPS are feasible, acceptable, and effective treatments for mild-to-moderate depression in the school setting. In addition, IPC seems effective even if comorbid anxiety exists. Our study shows that brief, structured interventions, such as IPC and BPS, are beneficial in treating mild-to-moderate depression in school settings and can be administered by professionals working at school.

Trial registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT03001245.