Trial protocol for the Building Resilience through Socio-Emotional Training (ReSET) programme: a cluster randomised controlled trial of a new transdiagnostic preventative intervention for adolescents.

BACKGROUND: Adolescence is a period of heightened vulnerability to developing mental health problems, and rates of mental health disorder in this age group have increased in the last decade. Preventing mental health problems developing before they become entrenched, particularly in adolescents who are at high risk, is an important research and clinical target. Here, we report the protocol for the trial of the 'Building Resilience through Socioemotional Training' (ReSET) intervention. ReSET is a new, preventative intervention that incorporates individual-based emotional training techniques and group-based social and communication skills training. We take a transdiagnostic approach, focusing on emotion processing and social mechanisms implicated in the onset and maintenance of various forms of psychopathology. METHODS: A cluster randomised allocation design is adopted with randomisation at the school year level. Five-hundred and forty adolescents (aged 12-14) will be randomised to either receive the intervention or not (passive control). The intervention is comprised of weekly sessions over an 8-week period, supplemented by two individual sessions. The primary outcomes, psychopathology symptoms and mental wellbeing, will be assessed pre- and post-intervention, and at a 1-year follow-up. Secondary outcomes are task-based assessments of emotion processing, social network data based on peer nominations, and subjective ratings of social relationships. These measures will be taken at baseline, post-intervention and 1-year follow-up. A subgroup of participants and stakeholders will be invited to take part in focus groups to assess the acceptability of the intervention. DISCUSSION: This project adopts a theory-based approach to the development of a new intervention designed to target the close connections between young people's emotions and their interpersonal relationships. By embedding the intervention within a school setting and using a cluster-randomised design, we aim to develop and test a feasible, scalable intervention to prevent the onset of psychopathology in adolescence. TRIAL REGISTRATION: ISRCTN88585916. Trial registration date: 20/04/2023.

The Future of CMC Regulatory Submissions: Streamlining Activities Using Structured Content and Data Management.

Recent advancements in data engineering, data science, and secure cloud storage can transform the current state of global Chemistry, Manufacturing, and Controls (CMC) regulatory activities to automated online digital processes. Modernizing regulatory activities will facilitate simultaneous global submissions and concurrent collaborative reviews, significantly reducing global licensing timelines and variability in globally registered product details. This article describes advancements made within the pharmaceutical industry from theoretical concepts to utilization of structured content and data in CMC submissions. The term Structured Content and Data Management (SCDM) outlines the end-to-end scientific data lifecycle from capture in source systems, aggregation into a consolidated repository, and transformation into semantically structured blocks with metadata defining relationships between scientific data and business contexts. Automation of regulatory authoring (termed Structured Content Authoring) is feasible because SCDM makes data both human and machine readable. It will offer health authorities access to the digital data beyond the current standard of PDF documents and, for a review process, SCDM would "enrich the effectiveness, efficiency, and consistency of regulatory quality oversight" (Yu et al., 2019). SCDM is a novel solution for content and data management in regulatory submissions and can enable faster access to critical therapies worldwide.

Merkel cell polyomavirus T antigens promote cell proliferation and inflammatory cytokine gene expression.

Merkel cell polyomavirus (MCV) is clonally integrated in over 80 % of Merkel cell carcinomas and mediates tumour development through the expression of viral oncoproteins, the large T (LT) and small T antigens (sT). Viral integration is associated with signature mutations in the T-antigen locus that result in deletions of C-terminal replicative functions of the LT antigen. Despite these truncations, the LT LXCXE retinoblastoma (Rb) pocket protein family binding domain is retained, and the entire sT isoform is maintained intact. To investigate the ability of MCV oncoproteins to regulate host gene expression, we performed microarray analysis on cells stably expressing tumour-derived LT, tumour-derived LT along with sT, and tumour-derived LT with a mutated Rb interaction domain. Gene expression alterations in the presence of tumour-derived LT could be classified into three main groups: genes that are involved in the cell cycle (specifically the G1/S transition), genes involved in DNA replication and genes involved in cellular movement. The LXCXE mutant LT largely reversed gene expression alterations detected with the WT tumour-derived LT, while co-expression of sT did not significantly affect these patterns of gene expression. LXCXE-dependent upregulation of cyclin E and CDK2 correlated with increased proliferation in tumour-derived LT-expressing cells. Tumour-derived LT and tumour-derived LT plus sT increased expression of multiple cytokines and chemokines, which resulted in elevated levels of secreted IL-8. We concluded that, in human fibroblasts, the LXCXE motif of tumour-derived LT enhances cellular proliferation and upregulates cell cycle and immune signalling gene transcription.

Human papillomavirus species-specific interaction with the basement membrane-resident non-heparan sulfate receptor.

Using a cell culture model where virus is bound to the extracellular matrix (ECM) prior to cell surface binding, we determined that human papillomavirus type 16 (HPV16) utilizes ECM resident laminin (LN) 332 as an attachment receptor for infectious entry. In presence of LN332, soluble heparin can function as ligand activator rather than competitive inhibitor of HPV16 infection. We also show that the ability to use LN332 binding as a productive attachment step for infectious entry is not conserved amongst HPV types. In the alpha genus, species 9 members (HPV16) attach to ECM via LN332, while members of species 7 (HPV18) are completely inhibited by heparin pre-incubation due to an inability to use LN332. Since HPV species 7 and 9 are preferentially associated with adenocarcinoma and squamous cell carcinoma of the cervix, respectively, our data provide first evidence that pre-entry events may contribute to the anatomical-site preference of HPV species.

Multiple heparan sulfate binding site engagements are required for the infectious entry of human papillomavirus type 16.

Human papillomavirus (HPV) entry is accompanied by multiple receptor-induced conformational changes (CCs) affecting both the major and minor capsid proteins, L1 and L2. Interaction of heparan sulfate (HS) with L1 is essential for successful HPV16 entry. Recently, cocrystallization of HPV16 with heparin revealed four distinct binding sites. Here we characterize mutant HPV16 to delineate the role of engagement with HS binding sites during infectious internalization. Site 1 (Lys278, Lys361), which mediates primary binding, is sufficient to trigger an L2 CC, exposing the amino terminus. Site 2 (Lys54, Lys356) and site 3 (Asn57, Lys59, Lys442, Lys443) are engaged following primary attachment and are required for infectious entry. Site 2 mutant particles are efficiently internalized but fail to undergo an L1 CC on the cell surface and subsequent uncoating in the endocytic compartment. After initial attachment to the cell, site 3 mutants undergo L1 and L2 CCs and then accumulate on the extracellular matrix (ECM). We conclude that the induction of CCs following site 1 and site 2 interactions results in reduced affinity for the primary HS binding site(s) on the cell surface, which allows engagement with site 3. Taken together, our findings suggest that HS binding site engagement induces CCs that prepare the virus for downstream events, such as the exposure of secondary binding sites, CCs, transfer to the uptake receptor, and uncoating.

A preliminary evaluation of the effectiveness of the Cystic Fibrosis Foundation Mentoring Program for Respiratory Care.

BACKGROUND: In 2008 the Cystic Fibrosis (CF) Foundation launched the Respiratory Therapy Mentoring Program, which pairs a respiratory therapist (RT) relatively new to CF (apprentice) with a highly experienced RT (mentor) from a similar CF care center. We wished to determine if we had achieved our short-term goal of increasing CF-specific knowledge among the apprentices who participated in the program. METHODS: Selected apprentices were each matched with a mentor, based on characteristics of CF population, clinical setting, center size, and geographic location of their care centers. Apprentices completed a CF-specific RT knowledge self assessment tool prior to and after a site visit to their mentor's center. Mentors also completed a post site visit knowledge self assessment tool regarding their apprentice. RESULTS: Thirty-seven apprentices completed a pre and post site visit knowledge self assessment tool. The median pre and post site visit scores were 12 and 31 (P < .001) respectively. The mentors' post site visit scores of their apprentices (median 29, P = .07) did not significantly differ from the apprentices' post site visit scores. CONCLUSIONS: The results of this preliminary evaluation suggest that the RT mentoring program has achieved its short-term goal of increasing CF-specific knowledge among RTs relatively new to CF care.

A comparison of methods for measuring spinal motion in female patients with adolescent idiopathic scoliosis.

Noninvasive surface measures of spine motion are validated in adult patients but are infrequently used in adolescent scoliosis patients. The agreement between surface and radiographic measurements of spinal motion is not known. We performed a comparative prospective analysis of 3 methods to measure spinal motion in female patients with adolescent idiopathic scoliosis (AIS) to establish normative data of spinal motion in AIS patients and evaluate the relationship between surface and radiographic measurements of spine motion. Measurements were obtained using a cloth tape measure, dual inclinometers, and a 3-dimensional electrogoniometer in 37 female patients with AIS. Radiographic parameters of the deformity were correlated with the spine motion. Differences between methods were evaluated by paired t tests. The Bland-Altman method was applied to evaluate agreement in measuring flexion. The average spinal flexion was 5.7 +/- 2.2 cm by the modified Schober method, 49 +/- 11 degrees by the dual inclinometers method, and 64 +/- 10 degrees by the 3-dimensional electrogoniometer. Spinal motion did not vary with magnitude of the scoliosis. In addition, surface measurements of spinal motion did not correlate with radiographic measurements of scoliosis flexibility. In this study, the amount of spinal motion varied, depending on the method of measurement. Surface measurements of motion cannot predict the magnitude or flexibility of the scoliosis.

The Bryan-Morrey triceps-sparing approach to open reduction of T-condylar humeral fractures in adolescents: cybex evaluation of triceps function and elbow motion.

Nine patients who underwent open reduction of a T-condylar distal humerus fracture through a Bryan-Morrey triceps-sparing approach were evaluated for triceps function and elbow motion. The average follow-up was 3 years 5 months. The average range of motion was -8 degrees to 136 degrees. Measured by Cybex testing, the average triceps deficit compared with the uninvolved arm was 6% at 60 degrees/sec, 7% at 120 degrees/sec, and 10% at 180 degrees/sec. Compared with another study that tested triceps function after open reduction with the Campbell triceps-splitting approach, no statistically significant difference in function or range of motion was found. In this small series, early postoperative continuous passive motion was found to significantly increase range of motion. The Bryan-Morrey triceps-sparing approach can be used in children and adolescents who require open reduction for T-condylar distal humeral fractures.