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Transgender and gender diverse (TGD) social work students experience microaggressions on campuses, curricula that are often cissexist and stigmatizing, and a lack of inclusive facilities, like gender-neutral bathrooms. The Transgender Justice Group (TJG) was founded by students at a School of Social Welfare (SSW) to respond to these and other pressing issues on the campus of a public university in the Midwestern U.S. This report aims to describe the formation process and activities of the TJG and provide recommendations for students, staff, and faculty who are interested in creating similar groups at other universities. Students and supporting faculty used a nonhierarchical approach to define, strategize, and implement advocacy goals, including creating more trans-affirming classrooms and increasing positive and proactive administrative responses to recent harmful anti-trans laws. Strategies for achieving these goals included engagement with a private, student-only online group chat, the production of regular informational webinars, and student-led meetings with school administrators to formally address state political actions negatively affecting TGD and queer people. Our group benefited from a dual focus on student support and advocacy. Through the TJG's ongoing work, students learned to collaborate more effectively, a skill that is crucial for their careers in the social work profession.

Podolian cattle is an autochthonous breed well adapted to the harsh semi-arid environments of the Southern Italy regions; the extensive rearing system used for these indigenous animals is based on grazing on spontaneous pastures, such as grasslands or wood pastures These grazing systems respect animal welfare and enrich animal products with characteristics closely related to the feeding system and the farming environment. The aim of the present study was to characterize the nutritional value of a forage crop and a wood-pasture and to evaluate the effects of grazing by Podolian young bulls on the performances and meat quality in relation to the age at slaughter (14 or 18 months) and to the ageing time of meat (3, 9 or 14 days). The metabolizable energy and the gas production were greater in April and June for both pasture systems. Young bulls raised on the grassland showed greater slaughter weights (p

Lichen sclerosus (LS) is a chronic inflammatory disease of the skin, and the gold standard for treatment is the use of the very potent topical steroids, but they can have side effects. Previously, we demonstrated that OZOILE (stable ozonides) were effective in children affected by LS, reducing the inflammatory process and stimulating tissue regeneration of the foreskin, showing a similar efficacy to steroid treatment. In this study, the modulation of inflammatory and oxidative stress pathways was evaluated by qRT-PCR and Western blotting in foreskins affected by LS removed from patients untreated or treated with OZOILE or corticosteroid cream formulations for 7 days before circumcision. OZOILE induced a significant increase in NRF2 and SOD2 levels, while it did not produce change in MIF, NF-kB subunits, and MMPs in comparison to untreated foreskins. Conversely, steroid topical treatment produced a significant reduction in the expression of p65, MIF, and MMP9, but it did not cause variation in NRF2 and SOD2 levels. These results demonstrate that the use of OZOILE as cream formulation exhibits effects on NRF2 signaling, and it does not induce NF-κB activation, unlike corticosteroids. On the basis of our biochemical data, further studies evaluating the role of NRF2 signaling cascade are necessary.

Abstract Hydrocephalus is a commonly encountered pathology in the neurosurgical practice. Since the first permanent ventriculo-subarachnoid-subgaleal shunt described by Mikulicz in 1893, there were multiple attempts to find solutions for draining the excess production/less reabsorption of the cerebrospinal fluid (CSF) from the brain. Nowadays, the most common technique is the ventriculoperitoneal shunt (VPS), whereas the ventriculoatrial shunt (VAS) is applied only in some rare conditions. To date there are still no specific guidelines or strong evidence in literature that guide the surgeon in the choice between the two methods, and the decision usually relies on the confidence and expertise of the surgeon. Considering the lack of established recommendations, this systematic review and meta-analysis aims to evaluate the effectiveness and safety of these two shunting techniques. This systematic review was conducted following the PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). No chronological limits of study publications were included. Prospective and retrospective clinical studies, and reports of case series with at least five patients per group and reporting data on comparison between VAS and VPS techniques were eligible for inclusion. Nine studies reporting 3197 patients meeting the inclusion and exclusion criteria were identified and included in the quantitative synthesis. The risk of shunt dysfunction/obstruction was significantly lower in the VAS group [odds ratio (OR) 0.49, 95%-CI 0.34–0.70, I2 0%]. The risk of infection was not significantly different between the two groups (OR 1.02, 95%-CI 0.59–1.74, I2 0%). The risk of revision was not significantly different between the two groups; however, the heterogeneity between the studies was significant (OR 0.73, 95%-CI 0.36–1.49, I2 91%). Additionally, the risk of death was not significantly different between the two groups; however, the heterogeneity between the studies was high (OR 1.93, 95%-CI 0.81–4.62, I2 64%). VAS remains a safe surgical alternative for hydrocephalus. The results of this study highlight a lower risk of shunt dysfunction/obstruction variable in the VAS group, with no significant statistical differences regarding the occurrence of at least one infection-related complication. In consequence, the choice between these two techniques must be tailored to the specific characteristics of the patient. Protocol Registration: The review protocol was registered and published in Prospective Register of Systematic Reviews (PROSPERO) ( www.crd.york.ac.uk/PROSPERO ) website with registration number: CRD42023479365.

Abstract Background The Mediterranean diet (MD), known to prevent obesity, overweight and the related non communicable diseases (NCD), is based on typical dishes, foods and on a common cultural milieu. Although MD is the basis of dietary guidelines, the prevalence of obesity, overweight and NCD, is increasing both in Western regions, and even more in Middle Eastern regions (MER). This study aimed to analyze (i) the impact of different levels of adherence to the MD, in Italy and MER, on body mass index (BMI) (ii) the bromatological composition of a simulated 7-days food plan (7-DFP) based on Italian or MER typical meals, following MD criteria and the Italian or MER food base dietary guideline; (iii) the optimization of nutrients impacting on NCD. Methods The 7-DFPs were implemented using a dietary software. The association between adherence to MD and BMI was evaluated by pooled estimated ORs (with 95% confidence intervals and p-values). Pooled measures were obtained by the methods appropriate for meta-analysis. The different food-based guidelines have been compared. Results The pooled ORs of obese status comparing medium vs. high adherence to MD were: 1.19 (95% C.I.: 0.99; 1.42, p-value = 0.062) and 1.12 (95% C.I.: 0.90; 1.38, p-value = 0.311) for MER and Italy respectively. For the comparison of low vs. high adherence, the pooled ORs were 1.05 (95% C.I.: 0.88; 1.24, p-value = 0.598) for MER, and 1.20 (95% C.I.: 1.02; 1.41, p-value = 0.031) for Italy when outliers are removed. High adherence to the MD resulted as potential protective factor against obesity. In MER 7-DFP: total fats is higher (34.5 E%) vs. Italian 7-DFP (29.4 E%); EPA (20 mg) and DHA (40 mg) are lower than recommended (200 mg each); sugars (12.6 E%) are higher than recommended (

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with an aggressive metastatic phenotype and very poor clinical prognosis. Interestingly, a lower occurrence of PDAC has been described in individuals with severe and long-standing asthma. Here we explored the potential link between PDAC and the glucocorticoid (GC) budesonide, a first-line therapy to treat asthma. Methods We tested the effect of budesonide and the classical GCs on the morphology, proliferation, migration and invasiveness of patient-derived PDAC cells and pancreatic cancer cell lines, using 2D and 3D cultures in vitro. Furthermore, a xenograft model was used to investigate the effect of budesonide on PDAC tumor growth in vivo. Finally, we combined genome-wide transcriptome analysis with genetic and pharmacological approaches to explore the mechanisms underlying budesonide activities in the different environmental conditions. Results We found that in 2D culture settings, high micromolar concentrations of budesonide reduced the mesenchymal invasive/migrating features of PDAC cells, without affecting proliferation or survival. This activity was specific and independent of the Glucocorticoid Receptor (GR). Conversely, in a more physiological 3D environment, low nanomolar concentrations of budesonide strongly reduced PDAC cell proliferation in a GR-dependent manner. Accordingly, we found that budesonide reduced PDAC tumor growth in vivo. Mechanistically, we demonstrated that the 3D environment drives the cells towards a general metabolic reprogramming involving protein, lipid, and energy metabolism (e.g., increased glycolysis dependency). This metabolic change sensitizes PDAC cells to the anti-proliferative effect of budesonide, which instead induces opposite changes (e.g., increased mitochondrial oxidative phosphorylation). Finally, we provide evidence that budesonide inhibits PDAC growth, at least in part, through the tumor suppressor CDKN1C/p57Kip2. Conclusions Collectively, our study reveals that the microenvironment influences the susceptibility of PDAC cells to GCs and provides unprecedented evidence for the anti-proliferative activity of budesonide on PDAC cells in 3D conditions, in vitro and in vivo. Our findings may explain, at least in part, the reason for the lower occurrence of pancreatic cancer in asthmatic patients and suggest a potential suitability of budesonide for clinical trials as a therapeutic approach to fight pancreatic cancer.

BackgroundBreast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.AimTo assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.MethodsAnalyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.ResultsThere was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].ConclusionSystemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Summary: The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1− neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines maintain CX3CR1+CD206+ macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1+CD206+ macrophages and induction of neoAg-specific CD8 T cells. Our findings highlight different mechanisms underlying neoAg vaccines and different forms of ICT and identify combinatorial therapies to enhance neoAg vaccine efficacy.

Objective: The Australian Government Tackling Indigenous Smoking (TIS) program aims to reduce tobacco use among Aboriginal and Torres Strait Islander peoples, delivering locally tailored health promotion messages, including promoting the Quitline. We aimed to analyse data on use of the Quitline by Aboriginal and Torres Strait Islander peoples nationally, specifically in TIS and non-TIS areas. Methods: We analysed usage of the Quitline in seven jurisdictions across Australia in areas with and without TIS teams (TIS areas and non-TIS areas respectively) between 2016–2020. Demographic and usage characteristics were quantified. Clients and referrals as a proportion of the current smoking population were calculated for each year, 2016–2020. Results: From 2016–2020, 12 274 Aboriginal and Torres Strait Islander people were clients of the Quitline in included jurisdictions. Most (69%) clients were living in a TIS area. Two-thirds (66.4%) of referrals were from third‑party referrers rather than self-referrals. Overall, between 1.25% and 1.62% of Aboriginal and Torres Strait Islander peoples who currently smoked were clients of Quitline (between 1.15–1.57% in TIS areas and 0.82–0.97% in non-TIS areas). Conclusions: The Quitline provided smoking cessation support to approximately 2500–3000 Aboriginal and Torres Strait Islander clients annually between 2016–2020. Referrals from third parties including Aboriginal and Torres Strait Islander services are an important pathway connecting community members to an evidenced-based cessation support service.

Flying Start (FS) is the Welsh Government’s targeted Early Years programme for families with children under 4 years of age who live in some of the most disadvantaged areas of Wales. The programme aims to mitigate the impact of poverty which is linked to poor life outcomes in early childhood. In particular, this study aims to investigate the impact of FS programme on FS children’s health outcomes in the form of Body Mass Index (BMI) and immunisation uptake, using linking analysis. The datasets linked to the FS cohort are respectively the Child Measurement Programme (CMP) and the National Community Child Health (NCCH). CMP consists of routinely taking height and weight measures of children in reception year to monitor BMI, whereas the NCCH is used to monitor health surveillance programmes, including immunisation. This project will use linked data to investigate the prevalence of fully immunised children across different levels of engagement with FS programme (normal and under-engagement). It will also look at prevalence of different BMI thresholds (underweight, overweight, and normal weight) and differences in mean BMI scores by FS programme engagement levels. In particular, chi-square will be used to explore differences in the proportion of fully immunised children and BMI thresholds, and t-test will be used to identify between-group differences in mean BMI scores. Results from this programme will inform of long-term health outcomes in relation to Early Years programmes. It will also help policy target resources and inform relevant interventions to support the healthy growth of children.

The Welsh Government funds a wide range of Early Years programmes to both support parents to remain in work and children’s social, emotional and educational development. The interest of Welsh Ministers in this policy area has grown in recent years with expansions in this area carefully considered. The potential for expanding the offer has generated a greater need for evidence to understand the effectiveness of the delivery against the proposed objectives. Data linking is a valuable and efficient way to provide complex evaluations of policy programmes as it maximises the use of existing data sources without increasing the burdens on data providers and provides comprehensive information that would otherwise be limited with a single dataset. However, Welsh Government research on programme evaluation in Early Years is facing challenges and this work aims at providing an overview of these issues, their impact on Early Years analytical work and progress made to address them. In particular, the main challenges are related to data quality and data availability that stem from lack of metadata and contextual information, poor technological infrastructure and, at times, a disconnect between policy / operational delivery and data collection. Progress is being made to address these challenges, such as acquiring new datasets or improving the quality of existing ones but these developments take time. At the same time as helping to tackle these structural challenges, the Early Years analytical team is exploring a range of novel approaches to provide robust evaluation of Early Years interventions despite the data issues.

The significant advancement that medicine has achieved in the past century is the transition from a focus on ''treating the sick'' to a focus on ''caring for health.'' The focus of pediatric primary care (PPC) is to care for the health and well-being of infants, children, and adolescents in their environment. It places emphasis on their autonomy and personal well-being while also involving parents, guardians, and caregivers. They provide this care within their family, community, and culture. Primary care pediatricians (PCPs) play a vital role in tackling global child health issues such as complex and chronic non-communicable diseases or refugee children. The primary focus of the ECPCP core curriculum for PCPs and the WHO's Pocketbook is to highlight the importance of enhancing primary healthcare, namely through the integration of comprehensive management for all pediatric disorders and conditions. PCPs should receive training on accessibility, closeness, continuity, and trust, as well as collaboration with related specialists. The ECPCP curriculum emphasizes fundamental subjects and abilities that are crucial for future PCPs.

Process Mining offers a powerful framework for uncovering, analyzing, and optimizing real-world business processes. Petri nets provide a versatile means of modeling process behavior. However, traditional methods often struggle to effectively compare complex Petri nets, hindering their potential for process enhancement. To address this challenge, we introduce PetriNet2Vec, an unsupervised methodology inspired by Doc2Vec. This approach converts Petri nets into embedding vectors, facilitating the comparison, clustering, and classification of process models. We validated our approach using the PDC Dataset, comprising 96 diverse Petri net models. The results demonstrate that PetriNet2Vec effectively captures the structural properties of process models, enabling accurate process classification and efficient process retrieval. Specifically, our findings highlight the utility of the learned embeddings in two key downstream tasks: process classification and process retrieval. In process classification, the embeddings allowed for accurate categorization of process models based on their structural properties. In process retrieval, the embeddings enabled efficient retrieval of similar process models using cosine distance. These results demonstrate the potential of PetriNet2Vec to significantly enhance process mining capabilities.

The short arms of the human acrocentric chromosomes 13, 14, 15, 21 and 22 (SAACs) share large homologous regions, including ribosomal DNA repeats and extended segmental duplications1,2. Although the resolution of these regions in the first complete assembly of a human genome-the Telomere-to-Telomere Consortium's CHM13 assembly (T2T-CHM13)-provided a model of their homology3, it remained unclear whether these patterns were ancestral or maintained by ongoing recombination exchange. Here we show that acrocentric chromosomes contain pseudo-homologous regions (PHRs) indicative of recombination between non-homologous sequences. Utilizing an all-to-all comparison of the human pangenome from the Human Pangenome Reference Consortium4 (HPRC), we find that contigs from all of the SAACs form a community. A variation graph5 constructed from centromere-spanning acrocentric contigs indicates the presence of regions in which most contigs appear nearly identical between heterologous acrocentric chromosomes in T2T-CHM13. Except on chromosome 15, we observe faster decay of linkage disequilibrium in the pseudo-homologous regions than in the corresponding short and long arms, indicating higher rates of recombination6,7. The pseudo-homologous regions include sequences that have previously been shown to lie at the breakpoint of Robertsonian translocations8, and their arrangement is compatible with crossover in inverted duplications on chromosomes 13, 14 and 21. The ubiquity of signals of recombination between heterologous acrocentric chromosomes seen in the HPRC draft pangenome suggests that these shared sequences form the basis for recurrent Robertsonian translocations, providing sequence and population-based confirmation of hypotheses first developed from cytogenetic studies 50 years ago9.

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements typically characterized by repeated units of 1-6 bp. We leveraged whole-genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family of mice to map loci that modulate genome-wide patterns of new mutations arising during parent-to-offspring transmission at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and performed quantitative trait locus (QTL) analyses for each of these phenotypes. We identified a locus on Chromosome 13 at which strains inheriting the C57BL/6J (B) haplotype have a higher rate of STR expansions than those inheriting the DBA/2J (D) haplotype. The strongest candidate gene in this locus is Msh3, a known modifier of STR stability in cancer and at pathogenic repeat expansions in mice and humans, as well as a current drug target against Huntington's disease. The D haplotype at this locus harbors a cluster of variants near the 5' end of Msh3, including multiple missense variants near the DNA mismatch recognition domain. In contrast, the B haplotype contains a unique retrotransposon insertion. The rate of expansion covaries positively with Msh3 expression-with higher expression from the B haplotype. Finally, detailed analysis of mutation patterns showed that strains carrying the B allele have higher expansion rates, but slightly lower overall total mutation rates, compared with those with the D allele, particularly at tetranucleotide repeats. Our results suggest an important role for inherited variants in Msh3 in modulating genome-wide patterns of germline mutations at STRs.

PurposeA polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer.MethodsWomen with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment.ResultsThe PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent.ConclusionAn increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.

There has been tremendous progress in phased genome assembly production by combining long-read data with parental information or linked-read data. Nevertheless, a typical phased genome assembly generated by trio-hifiasm still generates more than 140 gaps. We perform a detailed analysis of gaps, assembly breaks, and misorientations from 182 haploid assemblies obtained from a diversity panel of 77 unique human samples. Although trio-based approaches using HiFi are the current gold standard, chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. Importantly, the majority of assembly gaps cluster near the largest and most identical repeats (including segmental duplications [35.4%], satellite DNA [22.3%], or regions enriched in GA/AT-rich DNA [27.4%]). Consequently, 1513 protein-coding genes overlap assembly gaps in at least one haplotype, and 231 are recurrently disrupted or missing from five or more haplotypes. Furthermore, we estimate that 6-7 Mbp of DNA are misorientated per haplotype irrespective of whether trio-free or trio-based approaches are used. Of these misorientations, 81% correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large segmental duplications. We also identify large-scale alignment discontinuities consistent with 11.9 Mbp of deletions and 161.4 Mbp of insertions per haploid genome. Although 99% of this variation corresponds to satellite DNA, we identify 230 regions of euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Such variable and incompletely assembled regions are important targets for future algorithmic development and pangenome representation.