Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer

BACKGROUND: BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model. METHODS: We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point. RESULTS: The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p\u2009=\u20090.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p\u2009=\u20090.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p\u2009=\u20090.03) and of death (p\u2009=\u20090.004). CONCLUSIONS: These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model

Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease : additional results from the AMBAR study

This study was designed to detect structural and functional brain changes in Alzheimer's disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) were performed. MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18 FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG. (AMBAR trial registration: EudraCT#: 2011-001,598-25; ClinicalTrials.gov ID: NCT01561053). The online version contains supplementary material available at 10.1007/s00259-022-05915-

Duration of untreated illness and bipolar disorder: time for a new definition? Results from a cross-sectional study

Background: We primarily aimed to explore the associations between duration of untreated illness (DUI), treatment response, and functioning in a cohort of patients with bipolar disorder (BD). Methods: 261 participants with BD were recruited. DUI was defined as months from the first affective episode to the start of a mood-stabilizer. The functioning assessment short test (FAST) scores and treatment response scores for lithium, valproate, or lamotrigine according to the Alda Scale Total Score (TS) were compared between patients with short (<24 months) or long DUI. Differences in FAST scores among good (GR; TS≥7), poor (PR; TS=2-6), or non-responders (NR; TS<2) to each mood-stabilizer were analyzed. Linear regression was computed using the FAST global score as the dependent variable. Results: DUI and FAST scores showed no statistically significant correlation. Patients with a longer DUI showed poorer response to lithium (Z=-3.196; p<0.001), but not to valproate or lamotrigine. Response to lithium (β=-1.814; p<0.001), number of hospitalizations (β=0.237; p<0.001), and illness duration (β=0.160; p=0.028) were associated with FAST total scores. GR to lithium was associated with better global functioning compared to PR or NR [H=27.631; p<0.001]. Limitations: The retrospective design could expose our data to a recall bias. Also, only few patients were on valproate or lamotrigine treatment. Conclusions: Poor functioning in BD could be the result of multiple affective relapses, rather than a direct effect of DUI. A timely diagnosis with subsequent effective prophylactic treatment, such as lithium, may prevent poor functional outcomes in real-world patients with BD

Strategies for implementing occupational eMental health interventions : scoping review

BACKGROUND: The implementation of eMental health interventions, especially in the workplace, is a complex process. Therefore, learning from existing implementation strategies is imperative to ensure improvements in the adoption, development, and scalability of occupational eMental health (OeMH) interventions. However, the implementation strategies used for these interventions are often undocumented or inadequately reported and have not been systematically gathered across implementations in a way that can serve as a much-needed guide for researchers. OBJECTIVE: The objective of this scoping review was to identify implementation strategies relevant to the uptake of OeMH interventions that target employees and detail the associated barriers and facilitation measures. METHODS: A scoping review was conducted. The descriptive synthesis was guided by the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework and the Consolidated Framework for Implementation Research. RESULTS: A total of 31 of 32,916 (0.09%) publications reporting the use of the web-, smartphone-, telephone-, and email-based OeMH interventions were included. In all, 98 implementation strategies, 114 barriers, and 131 facilitators were identified. The synthesis of barriers and facilitators produced 19 facilitation measures that provide initial recommendations for improving the implementation of OeMH interventions. CONCLUSIONS: This scoping review represents one of the first steps in a research agenda aimed at improving the implementation of OeMH interventions by systematically selecting, shaping, evaluating, and reporting implementation strategies. There is a dire need for improved reporting of implementation strategies and combining common implementation frameworks with more technology-centric implementation frameworks to fully capture the complexities of eHealth implementation. Future research should investigate a wider range of common implementation outcomes for OeMH interventions that also focus on a wider set of common mental health problems in the workplace. This scoping review’s findings can be critically leveraged by discerning decision-makers to improve the reach, effectiveness, adoption, implementation, and maintenance of OeMH interventions

Antibody conversion rates to SARS-CoV-2 in saliva from children attending summer schools in Barcelona, Spain.

Background: Surveillance tools to estimate viral transmission dynamics in young populations are essential to guide recommendations for school opening and management during viral epidemics. Ideally, sensitive techniques are required to detect low viral load exposures among asymptomatic children. We aimed to estimate SARS-CoV-2 infection rates in children and adult populations in a school-like environment during the initial COVID-19 pandemic waves using an antibody-based field-deployable and non-invasive approach. Methods: Saliva antibody conversion defined as ≥ 4-fold increase in IgM, IgA, and/or IgG levels to five SARS-CoV-2 antigens including spike and nucleocapsid constructs was evaluated in 1509 children and 396 adults by high-throughput Luminex assays in samples collected weekly in 22 summer schools and 2 pre-schools in 27 venues in Barcelona, Spain, from June 29th to July 31st, 2020. Results: Saliva antibody conversion between two visits over a 5-week period was 3.22% (49/1518) or 2.36% if accounting for potentially cross-reactive antibodies, six times higher than the cumulative infection rate (0.53%) assessed by weekly saliva RT-PCR screening. IgG conversion was higher in adults (2.94%, 11/374) than children (1.31%, 15/1144) (p=0.035), IgG and IgA levels moderately increased with age, and antibodies were higher in females. Most antibody converters increased both IgG and IgA antibodies but some augmented either IgG or IgA, with a faster decay over time for IgA than IgG. Nucleocapsid rather than spike was the main antigen target. Anti-spike antibodies were significantly higher in individuals not reporting symptoms than symptomatic individuals, suggesting a protective role against COVID-19. Conclusion: Saliva antibody profiling including three isotypes and multiplexing antigens is a useful and user-friendlier tool for screening pediatric populations to detect low viral load exposures among children, particularly while they are not vaccinated and vulnerable to highly contagious variants, and to recommend public health policies during pandemics

Design and development of a digital intervention for workplace stress and mental health (EMPOWER)

Purpose: We describe the design and development of the European Platform to Promote health and wellbeing in the workplace (EMPOWER) digital intervention that provides an integrative user programme meeting the needs of employees and employers in addressing work stress. Results: A user-centred design process was followed from January 2020 until November 2021. A tailored algorithm was developed to provide support at the individual employee level and the company level. Each element of the digital intervention was developed in English and then translated in Spanish, English, Polish and Finnish. The digital intervention consists of a website and a mobile application (app) that provides algorithm-based personalised content after assessing a user's somatic and psychological symptoms, work functioning, and psychosocial risk factors for work stress. It has a public section and an employer portal that provides recommendations to reduce psychosocial risks in their company based upon clustered input from employees. Usability testing was conducted and showed high ease of use and completion of tasks by participants. Conclusion: The EMPOWER digital intervention is a tailored multimodal intervention addressing wellbeing, work stress, mental and physical health problems, and work productivity. This will be used in a planned RCT in four countries to evaluate its effectiveness

Study protocol of EMPOWER : A Cluster Randomized trial of a multimodal eHealth intervention for promoting mental health in the workplace following a Stepped Wedge Trial Design

Objective: This article describes the EMPOWER study, a controlled trial aiming to determine the effectiveness and cost-effectiveness of an eHealth intervention to prevent common health problems and reduce presenteeism and absenteeism in the workplace. Intervention: The EMPOWER intervention spans universal, secondary and tertiary prevention and consists of an eHealth platform delivered via a website and a smartphone app designed to guide employees throughout different modules according to their specific profiles. Design: A stepped-wedge cluster randomized trial will be implemented in four countries (Finland, Poland, Spain and UK) with employees from small and medium enterprises (SMEs) and public agencies. Companies will be randomly allocated in one of three groups with different times at which the intervention is implemented. The intervention will last 7 weeks. Employees will answer several questionnaires at baseline, pre- and post-intervention and follow-up. Outcome measures: The main outcome is presenteeism. Secondary outcomes include depression, anxiety, insomnia, stress levels, wellbeing and absenteeism. Analyses will be conducted at the individual level using the intention-to-treat approach and mixed models. Additional analyses will evaluate the intervention effects according to gender, country or type of company. Cost-effectiveness and cost-utility analyses [based on the use of quality-adjusted life-years (QALYS)] will consider a societal, employers’ and employees’ perspective

Study protocol of EMPOWER: A cluster randomized trial of a multimodal eHealth intervention for promoting mental health in the workplace following a stepped wedge trial design

Objective: This article describes the EMPOWER study, a controlled trial aiming to determine the effectiveness and cost-effectiveness of an eHealth intervention to prevent common health problems and reduce presenteeism and absenteeism in the workplace. Intervention: The EMPOWER intervention spans universal, secondary and tertiary prevention and consists of an eHealth platform delivered via a website and a smartphone app designed to guide employees throughout different modules according to their specific profiles.Design: A stepped-wedge cluster randomized trial will be implemented in four countries (Finland, Poland, Spain and UK) with employees from small and medium enterprises (SMEs) and public agencies. Companies will be randomly allocated in one of three groups with different times at which the intervention is implemented. The intervention will last 7 weeks. Employees will answer several questionnaires at baseline, pre- and post-intervention and follow-up. Outcome measures: The main outcome is presenteeism. Secondary outcomes include depression, anxiety, insomnia, stress levels, wellbeing and absenteeism. Analyses will be conducted at the individual level using the intention-to-treat approach and mixed models. Additional analyses will evaluate the intervention effects according to gender, country or type of company. Cost-effectiveness and cost-utility analyses [based on the use of quality-adjusted life-years (QALYS)] will consider a societal, employers' and employees' perspective.</p

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/