A systematic review of combined surgery and brachytherapy approaches for children and young people with relapsed and refractory rhabdomyosarcoma (Local-REFoRMS).

Approximately one third of children with rhabdomyosarcoma relapse or have refractory disease. Treatment approaches include a combination of systemic therapies and local therapies, directed at tumour site(s). This review was conducted to evaluate the effectiveness and safety of the combination of surgery and brachytherapy as local therapy for treating children and young people with relapsed/refractory rhabdomyosarcoma. This review identified studies based on a previous systematic review looking at the treatments for children and young people under 18 years old with relapsed/refractory rhabdomyosarcoma. Studies conducted after 2000 were included. Survival outcomes, relapse rates, adverse events and functional outcomes were extracted. From 16,965 records identified in the baseline systematic review, 205 included the words 'AMORE' or 'brachytherapy', and were screened for eligibility in this substudy. Thirteen studies met the inclusion criteria for Local-REFoRMS, including over 55 relapsed and refractory rhabdomyosarcoma patients. Most studies were retrospective cohort studies conducted within Europe. Most patients had embryonal disease within the head and neck or bladder/prostate regions, and received local therapy for first relapse. Approximately one quarter of patients relapsed following surgery and brachytherapy, with local relapses occurring more than metastatic relapse. Adverse events and functional outcomes were infrequently reported, but related to the site of surgery and brachytherapy. Study quality was limited by inconsistent reporting and potential selection bias. Outcomes following surgery and brachytherapy for a selected group of relapsed and refractory rhabdomyosarcoma show reasonable benefits, but reporting was often unclear and based on small sample sizes.

A systematic review of early phase studies for children and young people with relapsed and refractory rhabdomyosarcoma: The REFoRMS-SR project.

Rhabdomyosarcoma is the commonest soft tissue sarcoma in children. Around one-third of children with rhabdomyosarcoma experience relapse or have refractory disease, which is associated with a poor prognosis. This systematic review of early phase studies in pediatric relapsed/refractory rhabdomyosarcoma was conducted to inform future research and provide accurate information to families and clinicians making difficult treatment choices. Nine databases and five trial registries were searched in June 2021. Early phase studies of interventions for disease control in patients under 18 years old with relapsed/refractory rhabdomyosarcoma were eligible. No language/geographic restrictions were applied. Studies conducted after 2000 were included. Survival outcomes, response rates, quality of life and adverse event data were extracted. Screening, data extraction and quality assessment (Downs and Black Checklist) were conducted by two researchers. Owing to heterogeneity in the included studies, narrative synthesis was conducted. Of 16,965 records screened, 129 published studies including over 1100 relapsed/refractory rhabdomyosarcoma patients were eligible. Most studies evaluated systemic therapies. Where reported, 70% of studies reported a median progression-free survival ≤6 months. Objective response rate was 21.6%. Adverse events were mostly hematological. One-hundred and seven trial registry records of 99 studies were also eligible, 63 of which report they are currently recruiting. Study quality was limited by poor and inconsistent reporting. Outcomes for children with relapsed/refractory rhabdomyosarcoma who enroll on early phase studies are poor. Improving reporting quality and consistency would facilitate the synthesis of early phase studies in relapsed/refractory rhabdomyosarcoma (PROSPERO registration: CRD42021266254).

International study of the Complex Stress Reaction Syndrome: Implications for transdiagnostic clinical practice.

BACKGROUND: The debate regarding diagnostic classification systems in psychiatry (categorial vs dimensional systems) has essential implications for the diagnosis, prevention and treatment of stress reactions. We previously found a unique pattern of stress reaction in a study executed during the coronavirus disease 2019 pandemic using large representative samples in two countries, and termed it the Complex Stress Reaction Syndrome (CSRS). AIM: To investigate CSRS, Type A (psychiatric symptoms, spanning anxiety, depression, stress symptoms, and post-traumatic stress disorder (PTSD)), with or without long-coronavirus disease (COVID) residuals (CSRS, Type B, neuropsychiatric symptoms spanning cognitive deficits and fatigue, excluding systemic symptoms). Our two-tailed hypothesis was that CSRS is a condition related to an unrecognized type of stress reaction in daily life in the general population (Type A) or that it is related to the severe acute respiratory syndrome coronavirus 2 infection and its long-COVID residuals (Type B). METHODS: 977 individuals in four continents (North America, Europe, Australia and the Middle East) completed the online study questionnaire in six languages using the Qualtrics platform. The study was managed by six teams in six countries that promoted the study on social media. The questionnaire assessed anxiety, depression, stress symptoms and PTSD (CSRS, Type A), cognitive deficits and fatigue (CSRS, Type B). The data were analyzed using Proportion Analyses, Multivariate Analysis of Co-Variance (MANCOVA), linear regression analyses and validated clinical cutoff points. RESULTS: The results of the Proportion Analyses showed that the prevalence of 4 symptoms spanning anxiety, depression, stress symptoms, and PTSD was significantly higher than the most prevalent combinations of fewer symptoms across 4 continents, age groups, and gender. This supports the transdiagnostic argument embedded in the CSRS (Type A). The same pattern of results was found in infected/recovered individuals. The prevalence of the 4 psychiatric symptoms combination was significantly greater than that of 5 and 6 symptoms, when adding cognitive deficits and fatigue, respectively. MANCOVA showed a significant three-way interaction (age × gender × continent). Further analyses showed that the sources of this three-way interaction were threefold relating to two sub-populations at-risk: (1) Individuals that self-identified as non-binary gender scored significantly higher on all 4 psychiatric symptoms of the CSRS, Type A at young age groups (< 50 years old) in North America compared to (self-identified) women and men located in the 4 continents studied, and to other ages across the adult life span; and (2) This pattern of results (CSRS, Type A) was found also in women at young ages (< 40 years old) in North America who scored higher compared to men and women in other continents and other ages. Linear regression analyses confirmed the MANCOVA results. CONCLUSION: These results show a combined mental health risk factor related to stress reactivity, suggesting that the CSRS is sensitive to populations at risk and may be applied to future identification of other vulnerable sub-populations. It also supports the transdiagnostic approach for more accurate prevention and treatment. Time will tell if such transdiagnostic syndromes will be part of the discussions on the next revisions of the traditional classification systems or whether the crisis in psychiatry further evolves.

Leveraging 3D Bioprinting and Photon-Counting Computed Tomography to Enable Noninvasive Quantitative Tracking of Multifunctional Tissue Engineered Constructs.

3D bioprinting is revolutionizing the fields of personalized and precision medicine by enabling the manufacturing of bioartificial implants that recapitulate the structural and functional characteristics of native tissues. However, the lack of quantitative and noninvasive techniques to longitudinally track the function of implants has hampered clinical applications of bioprinted scaffolds. In this study, multimaterial 3D bioprinting, engineered nanoparticles (NPs), and spectral photon-counting computed tomography (PCCT) technologies are integrated for the aim of developing a new precision medicine approach to custom-engineer scaffolds with traceability. Multiple CT-visible hydrogel-based bioinks, containing distinct molecular (iodine and gadolinium) and NP (iodine-loaded liposome, gold, methacrylated gold (AuMA), and Gd2 O3 ) contrast agents, are used to bioprint scaffolds with varying geometries at adequate fidelity levels. In vitro release studies, together with printing fidelity, mechanical, and biocompatibility tests identified AuMA and Gd2 O3 NPs as optimal reagents to track bioprinted constructs. Spectral PCCT imaging of scaffolds in vitro and subcutaneous implants in mice enabled noninvasive material discrimination and contrast agent quantification. Together, these results establish a novel theranostic platform with high precision, tunability, throughput, and reproducibility and open new prospects for a broad range of applications in the field of precision and personalized regenerative medicine.

Methacrylate-Modified Gold Nanoparticles Enable Non-Invasive Monitoring of Photocrosslinked Hydrogel Scaffolds.

Photocrosslinked hydrogels, such as methacrylate-modified gelatin (gelMA) and hyaluronic acid (HAMA), are widely utilized as tissue engineering scaffolds and/or drug delivery vehicles, but lack a suitable means for non-invasive, longitudinal monitoring of surgical placement, biodegradation, and drug release. Therefore, we developed a novel photopolymerizable X-ray contrast agent, methacrylate-modified gold nanoparticles (AuMA NPs), to enable covalent-linking to methacrylate-modified hydrogels (gelMA and HAMA) in one-step during photocrosslinking and non-invasive monitoring by X-ray micro-computed tomography (micro-CT). Hydrogels exhibited a linear increase in X-ray attenuation with increased Au NP concentration to enable quantitative imaging by contrast-enhanced micro-CT. The enzymatic and hydrolytic degradation kinetics of gelMA-Au NP hydrogels were longitudinally monitored by micro-CT for up to one month in vitro, yielding results that were consistent with concurrent measurements by optical spectroscopy and gravimetric analysis. Importantly, AuMA NPs did not disrupt the hydrogel network, rheology, mechanical properties, and hydrolytic stability compared with gelMA alone. GelMA-Au NP hydrogels were thus able to be bioprinted into well-defined three-dimensional architectures supporting endothelial cell viability and growth. Overall, AuMA NPs enabled the preparation of both conventional photopolymerized hydrogels and bioprinted scaffolds with tunable X-ray contrast for noninvasive, longitudinal monitoring of placement, degradation, and NP release by micro-CT.

Strengthening the clinical academic pathway: a systematic review of interventions to support clinical academic careers for doctors and dentists.

OBJECTIVE: Evaluate existing evidence on interventions intended to increase recruitment, retention and career progression within clinical academic (CA) careers, including a focus on addressing inequalities. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, Cochrane Controlled Register of Trials, PsycINFO and Education Resource Information Center searched October 2019. STUDY SELECTION: Eligible studies included qualified doctors, dentists and/or those with a supervisory role. Outcomes were defined by studies and related to success rates of joining or continuing within a CA career. DATA EXTRACTION AND SYNTHESIS: Abstract screening was supported by machine learning software. Full-text screening was performed in duplicate, and study quality was assessed. Narrative synthesis of quantitative data was performed. Qualitative data were thematically analysed. RESULTS: 148 studies examined interventions; of which 28 were included in the quantitative synthesis, 17 in the qualitative synthesis and 2 in both. Studies lacked methodological rigour and/or were hindered by incomplete reporting. Most were from North America. No study included in the syntheses evaluated interventions aimed at CA dentists.Most quantitative evidence was from multifaceted training programmes. These may increase recruitment, but findings were less clear for retention and other outcomes. Qualitative studies reported benefits of supportive relationships, including peers and senior mentors. Protected time for research helped manage competing demands on CAs. Committed and experienced staff were seen as key facilitators of programme success. Respondents identified several other factors at a programme, organisational or national level which acted as facilitators or barriers to success. Few studies reported on the effects of interventions specific to women or minority groups. CONCLUSIONS: Existing research is limited by rigour and reporting. Better evaluation of future interventions, particularly those intended to address inequalities, is required. Within the limits of the evidence, comprehensive multifaceted programmes of training, including protected time, relational and support aspects, appear most successful in promoting CA careers. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework: https://osf.io/mfy7a.