Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy.

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.

Chemokine profiling of melanoma-macrophage crosstalk identifies CCL8 and CCL15 as prognostic factors in cutaneous melanoma.

During cancer evolution, tumor cells attract and dynamically interact with monocytes/macrophages. To find biomarkers of disease progression in human melanoma, we used unbiased RNA sequencing and secretome analyses of tumor-macrophage co-cultures. Pathway analysis of genes differentially modulated in human macrophages exposed to melanoma cells revealed a general upregulation of inflammatory hallmark gene sets, particularly chemokines. A selective group of chemokines, including CCL8, CCL15, and CCL20, was actively secreted upon melanoma-macrophage co-culture. Because we previously described the role of CCL20 in melanoma, we focused our study on CCL8 and CCL15 and confirmed that in vitro both chemokines contributed to melanoma survival, proliferation, and 3D invasion through CCR1 signaling. In vivo, both chemokines enhanced primary tumor growth, spontaneous lung metastasis, and circulating tumor cell survival and lung colonization in mouse xenograft models. Finally, we explored the clinical significance of CCL8 and CCL15 expression in human skin melanoma, screening a collection of 67 primary melanoma samples, using multicolor fluorescence and quantitative image analysis of chemokine-chemokine receptor content at the single-cell level. Primary skin melanomas displayed high CCR1 expression, but there was no difference in its level of expression between metastatic and nonmetastatic cases. By contrast, comparative analysis of these two clinically divergent groups showed a highly significant difference in the cancer cell content of CCL8 (p = 0.025) and CCL15 (p < 0.0001). Kaplan-Meier curves showed that a high content of CCL8 or CCL15 in cancer cells correlated with shorter disease-free and overall survival (log-rank test, p < 0.001). Our results highlight the role of CCL8 and CCL15, which are highly induced by melanoma-macrophage interactions in biologically aggressive primary melanomas and could be clinically applicable biomarkers for patient profiling. © 2024 The Pathological Society of Great Britain and Ireland.

Comprehensive splicing analysis of the alternatively spliced CHEK2 exons 8 and 10 reveals three enhancer/silencer-rich regions and 38 spliceogenic variants.

Splicing is controlled by a large set of regulatory elements (SREs) including splicing enhancers and silencers, which are involved in exon recognition. Variants at these motifs may dysregulate splicing and trigger loss-of-function transcripts associated with disease. Our goal here was to study the alternatively spliced exons 8 and 10 of the breast cancer susceptibility gene CHEK2. For this purpose, we used a previously published minigene with exons 6-10 that produced the expected minigene full-length transcript and replicated the naturally occurring events of exon 8 [Δ(E8)] and exon 10 [Δ(E10)] skipping. We then introduced 12 internal microdeletions of exons 8 and 10 by mutagenesis in order to map SRE-rich intervals by splicing assays in MCF-7 cells. We identified three minimal (10-, 11-, 15-nt) regions essential for exon recognition: c.863_877del [ex8, Δ(E8): 75%] and c.1073_1083del and c.1083_1092del [ex10, Δ(E10): 97% and 62%, respectively]. Then 87 variants found within these intervals were introduced into the wild-type minigene and tested functionally. Thirty-eight of them (44%) impaired splicing, four of which (c.883G>A, c.883G>T, c.884A>T, and c.1080G>T) induced negligible amounts (<5%) of the minigene full-length transcript. Another six variants (c.886G>A, c.886G>T, c.1075G>A, c.1075G>T, c.1076A>T, and c.1078G>T) showed significantly strong impacts (20-50% of the minigene full-length transcript). Thirty-three of the 38 spliceogenic variants were annotated as missense, three as nonsense, and two as synonymous, underlying the fact that any exonic change is capable of disrupting splicing. Moreover, c.883G>A, c.883G>T, and c.884A>T were classified as pathogenic/likely pathogenic variants according to ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based criteria. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

Deconstructing neutrophil to lymphocyte ratio (NLR) in early breast cancer: lack of prognostic utility and biological correlates across tumor subtypes.

PURPOSE: The prognostic utility and biological correlates of neutrophil to lymphocyte ratio (NLR), a potential biomarker of the balance between immune response and the inflammatory status, are still uncertain in breast cancer (BC). METHODS: We analysed a cohort of 959 women with early breast cancer, mostly treated with neoadjuvant or adjuvant chemotherapy. Clinical and pathological data, survival, NLR (continuous and categorical) and stromal tumor infiltrating lymphocytes (sTIL) were evaluated. RESULTS: NLR was only weakly associated with Ki67, while no association was found for grade, histology, immunohistochemical subtype or stage. Lymphocyte infiltration of the tumor did not correlate with NLR (Rho: 0.05, p = 0.30). These results were similar in the whole group and across the different BC subtypes, with no differences in triple negative BC. Relapse free interval (RFI), breast cancer specific survival (BCSS) and overall survival (OS) changed according to pre-treatment NLR neither in the univariate nor in the multivariate Cox models (RFI: HR 0.948, p = 0.61; BCSS: HR 0.920, p = 0.57; OS: HR 0.96, p = 0.59). CONCLUSION: These results question the utility of NLR as a prognostic biomarker in early breast cancer and suggest the lack of correlation of NLR with tumor microenvironment immune response.

Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants.

BACKGROUND: Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes. METHODS: A total of 128 CHEK2 splice-site variants identified in the Breast Cancer After Diagnostic Gene Sequencing (BRIDGES) project (https://cordis.europa.eu/project/id/634935) were analyzed with MaxEntScan and subsetted to 52 variants predicted to impact splicing. Three CHEK2 minigenes, which span all 15 exons, were constructed and validated. The 52 selected variants were then genetically engineered into the minigenes and assayed in MCF-7 (human breast adenocarcinoma) cells. RESULTS: Of 52 variants, 46 (88.5%) impaired splicing. Some of them led to complex splicing patterns with up to 11 different transcripts. Thirty-four variants induced splicing anomalies without any trace or negligible amounts of the full-length transcript. A total of 89 different transcripts were annotated, which derived from different events: single- or multi-exon skipping, alternative site-usage, mutually exclusive exon inclusion, intron retention or combinations of the abovementioned events. Fifty-nine transcripts were predicted to introduce premature termination codons, 7 kept the original open-reading frame, 5 removed the translation start codon, 6 affected the 5'UTR (Untranslated Region), and 2 included missense variations. Analysis of variant c.684-2A > G revealed the activation of a non-canonical TG-acceptor site and exon 6 sequences critical for its recognition. CONCLUSIONS: Incorporation of minigene read-outs into an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme allowed us to classify 32 CHEK2 variants (27 pathogenic/likely pathogenic and 5 likely benign). However, 20 variants (38%) remained of uncertain significance, reflecting in part the complex splicing patterns of this gene.

Randomized controlled trials in nursing conducted by Latin American research teams: A scoping review.

INTRODUCTION: Randomized controlled trials (RCTs) are the cornerstone of systematic reviews and other evidence synthesis. RCT identification remains challenging because of limitations in their indexation in major databases and potential language bias. Scientific production in Latin American nursing is steadily increasing, but little is known about its design or main features. We aimed to identify the extent of evidence from RCTs in nursing conducted by Latin American research teams and evaluate their main characteristics, including potential risk of bias. DESIGN: Scoping review with risk of bias assessment. METHODS: We conducted a scoping review including a comprehensive electronic search in five relevant databases. We completed a descriptive data analysis and a risk of bias assessment of eligible studies using Cochrane's guidance. RESULTS: We identified 1784 references of which 47 were RCTs published in 40 journals. Twenty (42.6%) RCTs were published in journals in English. Chronic diseases were the most common health conditions studied (29.7%). Fifteen (31.9%) RCTs had a high risk of bias. Thirty (75%) journals were included in the Journal Citation Report (JCR) catalog and 5 (16.7%) were journals classified under nursing category. Twenty-one (52.5%) journals explicitly required CONSORT checklist recommendations for RCTs reporting. CONCLUSION: Publication of RCTs in nursing by Latin American authors has increased. Most journals where RCTs are published are in English and not specific to nursing. Searches in journals of other disciplines may be necessary to facilitate identification of RCTs in nursing. CONSORT statements need to be actively promoted to facilitate rigorous methodology and reporting of RCTs. CLINICAL RELEVANCE STATEMENT: This study highlights the need for an increased research focus on RCTs in nursing in Latin America, and the importance of enhancing the reporting quality of these studies to support evidence-based nursing practice.

Community Outbreak of Pseudomonas aeruginosa Infections Associated with Contaminated Piercing Aftercare Solution, Australia, 2021.

In April 2021, the South Eastern Sydney Local Health District Public Health Unit (Sydney, New South Wales, Australia) was notified of 3 patients with Pseudomonas aeruginosa infections secondary to skin piercings performed at the same salon. Active case finding through laboratories, clinician alerts, and monitoring hospital visits for piercing-related infections identified additional cases across New South Wales, and consumers were alerted. We identified 13 confirmed and 40 probable case-patients and linked clinical isolates by genomic sequencing. Ten confirmed case-patients had used the same brand and batch of aftercare solution. We isolated P. aeruginosa from opened and unopened bottles of this solution batch that matched the outbreak strain identified by genomic sequencing. Piercing-related infections returned to baseline levels after this solution batch was recalled. Early outbreak detection and source attribution via genomic sequencing are crucial for controlling outbreaks linked to contaminated products. Manufacturing standards for nonsterile cosmetic products and guidance for piercing aftercare warrant review.

The Frequency of Specific KRAS Mutations, and Their Impact on Treatment Choice and Survival, in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) and KRAS mutations have a poor prognosis, seemingly dependent on the location of the mutation. This multicenter, retrospective, cohort study assessed the frequency and prognostic value of specific KRAS mutation codon locations in mCRC patients, and survival outcomes in relation to treatment. MATERIALS AND METHODS: Data from mCRC patients treated in 10 Spanish hospitals between January 2011 and December 2015 were analyzed. The main objective was to investigate (1) the impact of KRAS mutation location on overall survival (OS), and (2) the effect of targeted treatment plus metastasectomy and primary tumor location on OS in patients with KRAS mutations. RESULTS: The KRAS mutation location was known for 337/2002 patients. Of these, 177 patients received chemotherapy only, 155 received bevacizumab plus chemotherapy, and 5 received anti-epidermal growth factor receptor therapy plus chemotherapy; 94 patients underwent surgery. The most frequent KRAS mutation locations were G12A (33.8%), G12D (21.4%), and G12V (21.4%). Compared with other locations, patients with a G12S mutation had the shortest median OS (10.3 [95% CI, 2.5-18.0] months). OS was longer in patients who underwent surgery versus those who did not, with a trend toward prolonged survival with bevacizumab (median OS 26.7 [95% CI, 21.8-31.7] months) versus chemotherapy alone (median OS 23.2 [95% CI, 19.4-27.0] months). CONCLUSION: These findings confirm that KRAS mutation location may predict survival outcomes in patients with mCRC, and suggest that pre-/post-operative bevacizumab plus metastasectomy provides survival benefits in patients with KRAS mutations.

Genomic markers of drug resistance in Mycobacterium tuberculosis populations with minority variants.

Minority variants of Mycobacterium tuberculosis harboring mutations conferring resistance can become dominant populations during tuberculosis (TB) treatment, leading to treatment failure. Our understanding of drug-resistant within-host subpopulations and the frequency of resistance-conferring mutations in minority variants remains limited. M. tuberculosis sequences recovered from liquid cultures of culture-confirmed TB cases notified between January 2017 and December 2021 in New South Wales, Australia were examined. Potential drug resistance-conferring minority variants were identified using LoFreq, and mixed populations of different M. tuberculosis strains (≥100 SNPs apart) were examined using QuantTB. A total of 1831 routinely sequenced M. tuberculosis strains were included in the analysis. Drug resistance-conferring minority variants were detected in 3.5% (65/1831) of sequenced cultures; 84.6% (55/65) had majority strains that were drug susceptible and 15.4% (10/65) had majority strains that were drug resistant. Minority variants with high-confidence drug resistance-conferring mutations were 1.5 times more common when the majority strains were drug resistant. Mixed M. tuberculosis strain populations were documented in 10.0% (183/1831) of specimens. Minority variants with high-confidence drug resistance-conferring mutations were more frequently detected in mixed M. tuberculosis strain populations (2.7%, 5/183) than in single strain populations (0.6%, 10/1648; P = 0.01). Drug-resistant minority variants require monitoring in settings that implement routine M. tuberculosis sequencing. The frequency with which drug-resistant minority variants are detected is likely influenced by pre-culture requirement. Culture-independent sequencing methods should provide a more accurate reflection of drug-resistant subpopulations.

Near real-time surveillance of the SARS-CoV-2 epidemic with incomplete data.

When responding to infectious disease outbreaks, rapid and accurate estimation of the epidemic trajectory is critical. However, two common data collection problems affect the reliability of the epidemiological data in real time: missing information on the time of first symptoms, and retrospective revision of historical information, including right censoring. Here, we propose an approach to construct epidemic curves in near real time that addresses these two challenges by 1) imputation of dates of symptom onset for reported cases using a dynamically-estimated "backward" reporting delay conditional distribution, and 2) adjustment for right censoring using the NobBS software package to nowcast cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number (Rt) in real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We evaluate how these real-time estimates compare with more complete epidemiological data that became available later. We explore the impact of the different assumptions on the estimates, and compare our estimates with those obtained from commonly used surveillance approaches. Our framework can help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health systems in other locations.

Minigene-based splicing analysis and ACMG/AMP-based tentative classification of 56 ATM variants.

The ataxia telangiectasia-mutated (ATM) protein is a major coordinator of the DNA damage response pathway. ATM loss-of-function variants are associated with 2-fold increased breast cancer risk. We aimed at identifying and classifying spliceogenic ATM variants detected in subjects of the large-scale sequencing project BRIDGES. A total of 381 variants at the intron-exon boundaries were identified, 128 of which were predicted to be spliceogenic. After further filtering, we ended up selecting 56 variants for splicing analysis. Four functional minigenes (mgATM) spanning exons 4-9, 11-17, 25-29, and 49-52 were constructed in the splicing plasmid pSAD. Selected variants were genetically engineered into the four constructs and assayed in MCF-7/HeLa cells. Forty-eight variants (85.7%) impaired splicing, 32 of which did not show any trace of the full-length (FL) transcript. A total of 43 transcripts were identified where the most prevalent event was exon/multi-exon skipping. Twenty-seven transcripts were predicted to truncate the ATM protein. A tentative ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme that integrates mgATM data allowed us to classify 29 ATM variants as pathogenic/likely pathogenic and seven variants as likely benign. Interestingly, the likely pathogenic variant c.1898+2T>G generated 13% of the minigene FL-transcript due to the use of a noncanonical GG-5'-splice-site (0.014% of human donor sites). Circumstantial evidence in three ATM variants (leakiness uncovered by our mgATM analysis together with clinical data) provides some support for a dosage-sensitive expression model in which variants producing ≥30% of FL-transcripts would be predicted benign, while variants producing ≤13% of FL-transcripts might be pathogenic. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants.

PALB2 loss-of-function variants confer high risk of developing breast cancer. Here we present a systematic functional analysis of PALB2 splice-site variants detected in approximately 113,000 women in the large-scale sequencing project Breast Cancer After Diagnostic Gene Sequencing (BRIDGES; https://bridges-research.eu/). Eighty-two PALB2 variants at the intron-exon boundaries were analyzed with MaxEntScan. Forty-two variants were selected for the subsequent splicing functional assays. For this purpose, three splicing reporter minigenes comprising exons 1-12 were constructed. The 42 potential spliceogenic variants were introduced into the minigenes by site-directed mutagenesis and assayed in MCF-7/MDA-MB-231 cells. Splicing anomalies were observed in 35 variants, 23 of which showed no traces or minimal amounts of the expected full-length transcripts of each minigene. More than 30 different variant-induced transcripts were characterized, 23 of which were predicted to truncate the PALB2 protein. The pathogenicity of all variants was interpreted according to an in-house adaptation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) variant classification scheme. Up to 23 variants were classified as pathogenic/likely pathogenic. Remarkably, three ±1,2 variants (c.49-2A>T, c.108+2T>C, and c.211+1G>A) were classified as variants of unknown significance, as they produced significant amounts of either in-frame transcripts of unknown impact on the PALB2 protein function or the minigene full-length transcripts. In conclusion, we have significantly contributed to the ongoing effort of identifying spliceogenic variants in the clinically relevant PALB2 cancer susceptibility gene. Moreover, we suggest some approaches to classify the findings in accordance with the ACMG-AMP rationale. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Linear and Non-linear Analyses of EEG in a Group of ASD Children During Resting State Condition.

This study analyses the spontaneous electroencephalogram (EEG) brain activity of 14 children diagnosed with Autism Spectrum Disorder (ASD) compared to 18 children with normal development, aged 5-11 years. (i) Power Spectral Density (PSD), (ii) variability across trials (coefficient of variation: CV), and (iii) complexity (multiscale entropy: MSE) of the brain signal analysis were computed on the resting state EEG. PSD (0.5-45 Hz) and CV were averaged over different frequency bands (low-delta, delta, theta, alpha, low-beta, high-beta and gamma). MSE were calculated with a coarse-grained procedure on 67 time scales and divided into fine, medium and coarse scales. In addition, significant neurophysiological variables were correlated with behavioral performance data (Kaufman Brief Intelligence Test (KBIT) and Autism Spectrum Quotient (AQ)). Results show increased PSD fast frequency bands (high-beta and gamma), higher variability (CV) and lower complexity (MSE) in children with ASD when compared to typically developed children. These results suggest a more variable, less complex and, probably, less adaptive neural networks with less capacity to generate optimal responses in ASD children.

Child and adolescent development of the brain oscillatory activity during a working memory task.

The developmental trajectories of brain oscillations during the encoding and maintenance phases of a Working Memory (WM) task were calculated. The Delayed-Match-to-Sample Test (DMTS) was applied to 239 subjects of 6-29 years, while EEG was recorded. The Event-Related Spectral Perturbation (ERSP) was obtained in the range between 1 and 25 Hz during the encoding and maintenance phases. Behavioral parameters of reaction times (RTs) and response accuracy were simultaneously recorded. The results indicate a myriad of transient and sustained bursts of oscillatory activity from low frequencies (1 Hz) to the beta range (up to 19 Hz). Beta and Low-frequency ERSP increases were prominent in the encoding phase in all age groups, while low-frequency ERSP indexed the maintenance phase only in children and adolescents, but not in late adolescents and young adults, suggesting an age-dependent neural mechanism of stimulus trace maintenance. While the latter group showed Beta and Alpha indices of anticipatory attention for the retrieval phase. Mediation analysis showed an important role of early Delta-Theta and late Alpha oscillations for mediation between age and behavioral responses performance. In conclusion, the results show a complex pattern of oscillatory bursts during the encoding and maintenance phases with a consistent pattern of developmental changes.

Three-year survival and distribution of lymph node metastases in gastric cancer following neoadjuvant chemotherapy: results from a European randomized clinical trial.

BACKGROUND: Adequate lymphadenectomy is an important step in gastrectomy for cancer, with a modified D2 lymphadenectomy being recommended for advanced gastric cancers. When assessing a novel technique for the treatment of gastric cancer, lymphadenectomy should be non-inferior. The aim of this study was to assess completeness of lymphadenectomy and distribution patterns between open total gastrectomy (OTG) and minimally invasive total gastrectomy (MITG) in the era of peri-operative chemotherapy. METHODS: This is a retrospective analysis of the STOMACH trial, a randomized clinical trial in thirteen hospitals in Europe. Patients were randomized between OTG and MITG for advanced gastric cancer after neoadjuvant chemotherapy. Three-year survival, number of resected lymph nodes, completeness of lymphadenectomy, and distribution patterns were examined. RESULTS: A total of 96 patients were included in this trial and randomized between OTG (49 patients) and MITG (47 patients). No difference in 3-year survival was observed, this was 57.1% in OTG group versus 46.8% in MITG group (P = 0.186). The mean number of examined lymph nodes per patient was 44.3 ± 16.7 in the OTG group and 40.7 ± 16.3 in the MITG group (P = 0.209). D2 lymphadenectomy of 71.4% in the OTG group and 74.5% in the MITG group was performed according to the surgeons; according to the pathologist compliance to D2 lymphadenectomy was 30% in the OTG group and 36% in the MITG group. Tier 2 lymph node metastases (stations 7-12) were observed in 19.6% in the OTG group versus 43.5% in the MITG group (P = 0.024). CONCLUSION: No difference in 3-year survival was observed between open and minimally invasive gastrectomy. No differences were observed for lymph node yield and type of lymphadenectomy. Adherence to D2 lymphadenectomy reported by the pathologist was markedly low.

Psychosocial changes during COVID-19 lockdown on nursing home residents, their relatives and clinical staff: a prospective observational study.

BACKGROUND: Previous works have observed an increase of depression and other psychological disorders on nursing home residents as a consequence of coronavirus disease 2019 (COVID-19) lockdown; however, there are few studies that have performed a comprehensive evaluation of all people involved in nursing homes environment. The objective of the work was to analyse the impact of lockdown on psychosocial factors of nursing home residents, relatives and clinical staff and how these variables have influenced residents' survival. METHODS: A prospective study was designed. Evaluations were performed at three different times: a) at the beginning of Spanish confinement, in March 2020; b) just before the second wave of the pandemic, with relaxation of security measures but in lockdown, and c) in January-February 2021, at the end of the second wave, when visits were already allowed. The study was conducted on three different nursing homes. Three hundred and one residents, 119 clinical staff and 51 relatives took part in the study. Anxiety and depression were evaluated in all participants. A scale on the meaning of suffering was also performed. In addition, burnout status was also determined in the clinical staff. RESULTS: All participants showed lower depression during lockdown, while at the beginning and at the end of the confinement, these values were significantly increased. In residents, these changes were dependent of cognitive status (p = 0.012). Anxiety was significantly higher in residents. The evolution of anxiety was similar than with depression, with lower values during confinement, although clinical staff showed higher anxiety levels at the beginning. The feeling of suffering was significantly lower in the clinical staff than in resident and relative groups. Residents' survival was dependent of cognitive status (p = 0.018) and voluntary confinement (p < 0.001). CONCLUSIONS: During the first COVID-19 lockdown, psychological wellbeing of residents cared in nursing homes, their relatives and staff did not seem to be seriously affected. Previous mental health in relatives and staff together with a resilient approach to the adversity might partly be protecting factors. The lack of consequences on residents' anxiety, depression and perception of social support may reflect the special attention and care they received. Finally, as in the current study only data of the first two COVID-19 waves were analysed, its findings might be partly generalized to all the pandemic.

Leadership and contagion by COVID-19 among residence hall students: A social network analysis approach.

University students have changed their behaviour due to the COVID-19 pandemic. In this paper, we describe the characteristics of PCR+ and PCR- nodes, analyse the structure, and relate the structure of student leaders to pandemic contagion as determined by PCR+ in 93 residential university students. Leadership comes from the male students of social science degrees who have PCR +, with an eigenvector centrality structure, ß-centrality, and who are part of the bow-tie structure. There was a significant difference in ß-centrality between leaders and non-leaders and in ß-centrality between PCR+ and non-leaders. Leading nodes were part of the bow-tie structure. MR-QAP results show how residence and scientific branch were the most important factors in network formation. Therefore, university leaders should consider influential leaders, as they are vectors for disseminating both positive and negative outcomes.

Can a gender-sensitive integrated poultry value chain and nutrition intervention increase women's empowerment among the rural poor in Burkina Faso?

Understanding the types of food systems interventions that foster women's empowerment and the types of women that are able to benefit from different interventions is important for development policy. SELEVER was a gender- and nutrition-sensitive poultry production intervention implemented in western Burkina Faso from 2017 to 2020 that aimed to empower women. We evaluated SELEVER using a mixed-methods cluster-randomized controlled trial, which included survey data from 1763 households at baseline and endline and a sub-sample for two interim lean season surveys. We used the multidimensional project-level Women's Empowerment in Agriculture Index (pro-WEAI), which consists of 12 binary indicators, underlying count versions of 10 of these, an aggregate empowerment score (continuous) and a binary aggregate empowerment indicator, all for women and men. Women's and men's scores were compared to assess gender parity. We also assessed impacts on health and nutrition agency using the pro-WEAI health and nutrition module. We estimated program impact using analysis of covariance (ANCOVA) models and examined whether there were differential impacts by flock size or among those who participated in program activities (treatment on the treated). Program impacts on empowerment and gender parity were null, despite the program's multipronged and gender-sensitive approach. Meanwhile, results of the in-depth gender-focused qualitative work conducted near the project mid-point found there was greater awareness in the community of women's time burden and their economic contributions, but it did not seem that awareness led to increased empowerment of women. We reflect on possible explanations for the null findings. One notable explanation may be the lack of a productive asset transfer, which have previously been shown to be essential, but not sufficient, for the empowerment of women in agricultural development programs. We consider these findings in light of current debates on asset transfers. Unfortunately, null impacts on women's empowerment are not uncommon, and it is important to learn from such findings to strengthen future program design and delivery.

Severe and refractory gastrointestinal toxicity due to immune checkpoint inhibitors: clinical experience in a tertiary referral hospital.

INTRODUCTION: immune checkpoint inhibitors (ICI) are increasingly used to treat several types of cancer. These drugs lead to a wide range of toxicities. Immune-related gastrointestinal adverse events are common and potentially severe. In this manuscript, we recount the real clinical experience in a tertiary center. METHODS: a retrospective and observational study was conducted in adult patients under ICI treatment. Included patients had been referred to the Gastrointestinal Service of Hospital Universitario Vall d'Hebron for evaluation of severe toxicities, from January 2017 to January 2020, for whom the clinical, epidemiological and evolutive data were collected. RESULTS: a total of 18 patients were included. Fifty-five percent received anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (anti PD-L1), 11 % received anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and 33 % received both treatments. The toxicities were manifested as enterocolitis, microscopic colitis and gastritis. Upper gastrointestinal endoscopy was performed in seven patients; all were proved to have histological changes on duodenum biopsies. Treatment was stopped in all patients and steroids were initiated. Sixty-six per cent achieved clinical remission with steroids. Five patients received anti-TNF treatment (infliximab). Only one of the five had responded. Two anti-TNF refractory patients received ustekinumab, with an appropriate clinical response. One patient received apheresis granulocyte as concomitant treatment. A patient with a steroid-dependent course started vedolizumab. Three patients had other immune-related adverse events. CONCLUSION: gastrointestinal immune-related adverse events are acquiring a higher profile in daily practice and gastroenterologists play an even greater role in the management of these patients.