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Background Falls in hospital remain a common and costly patient safety issue internationally. There is evidence that falls in hospitals can be prevented by multifactorial programs and by education for patients and staff, but these are often not routinely or effectively implemented in practice. Perspectives of multiple key stakeholder groups could inform implementation of fall prevention strategies. Methods Clinicians of different disciplines, patients and their families were recruited from wards at two acute public hospitals. Semi-structured interviews and focus groups were conducted to gain a broad understanding of participants' perspectives about implementing fall prevention programs. Data were analysed using an inductive thematic approach. Results Data from 50 participants revealed three key themes across the stakeholder groups shaping implementation of acute hospital fall prevention programs: (i) 'Fall prevention is a priority, but whose?' where participants agreed falls in hospital should be addressed but did not necessarily see themselves as responsible for this; (ii) 'Disempowered stakeholders' where participants expressed feeling frustrated and powerless with fall prevention in acute hospital settings; and (iii) 'Shared responsibility may be a solution' where participants were optimistic about the positive impact of collective action on effectively implementing fall prevention strategies. Conclusion Key stakeholder groups agree that hospital fall prevention is a priority, however, challenges related to role perception, competing priorities, workforce pressure and disempowerment mean fall prevention may often be neglected in practice. Improving shared responsibility for fall prevention implementation across disciplines, organisational levels and patients, family and staff may help overcome this. [ABSTRACT FROM AUTHOR]

Inequalities in diets contribute to overall inequalities in health. Economic inequality and inequalities in access to healthy food are key drivers of poor diet and ill health among young people (YP). Despite mounting evidence of structural barriers to healthy eating, less is known about how YP view and experience these inequalities where they live, and how to address them. To explore YP's perspectives on the drivers of diet-related health inequalities, we conducted three interlinked focus groups with YP aged 13–21 years from six youth groups across three geographical areas in England. We analysed the data inductively and deductively using reflexive thematic analysis and generated themes by examining how social structure, context and agency interact and impact YP's diet. YP were aware of how inequalities in employment conditions impact their families' income and ability to eat a healthy diet. They cited the high availability of hot food takeaways in their local areas as a significant barrier to healthy eating but did not support closing or restricting these outlets. They held strong views on policies to tackle diet inequality and showed a nuanced understanding of the strengths and limitations of universal and targeted approaches. Our study showed that YP have an awareness and understanding of food as important in relation to health, and of diet-related inequalities. However, further efforts are needed to shape and promote policies that resonate with YP and address both their health and wider social concerns. [ABSTRACT FROM AUTHOR]

Background: Oncoplastic breast-conserving surgery may allow women with early breast cancer to avoid a mastectomy, but many women undergo more extensive surgery, even when breast-conserving options are offered. The aim of the ANTHEM qualitative study was to explore factors influencing women's surgical decision-making for and against oncoplastic breast-conserving surgery. Methods: Semi-structured interviews were conducted with a purposive sample of women who had received either oncoplastic breast-conserving surgery or a mastectomy with or without immediate breast reconstruction to explore their rationale for procedure choice. Interviews were transcribed verbatim and analysed thematically. Trial registration number: ISRCTN18238549. Results: A total of 27 women from 12 centres were interviewed. Out of these, 12 had chosen oncoplastic breast-conserving surgery and 15 had chosen a mastectomy with or without immediate breast reconstruction. Overwhelmingly, women's decisions were guided by their surgical teams. Decision-making for and against oncoplastic breast-conserving surgery was influenced by three key inter-related factors: perceptions of oncological safety; the importance of maintaining/restoring femininity and body image; and practical issues. Oncological safety was paramount. Women who reported feeling reassured that oncoplastic breast-conserving surgery was oncologically safe were happy to choose this option. Those who were not reassured were more likely to opt for a mastectomy, as a perceived 'safer' option. Most women wished to maintain/restore femininity, with the offer of immediate breast reconstruction essential to make a mastectomy an acceptable option. Practical issues such as the perceived magnitude of the surgery were a lesser concern. Conclusion: Decision-making is complex and heavily influenced by the surgical team. High-quality, accurate information about surgical options, including appropriate reassurance about the short- and long-term oncological safety of oncoplastic breast-conserving surgery is vital if women are to make fully informed decisions. Perceived overestimation of the oncological benefits of a mastectomy and a lack of awareness of the potential short- and long-term issues associated with breast reconstruction raise concerns about the quality of the information provided to women making decisions about their options and the degree to which their decisions are fully informed. [ABSTRACT FROM AUTHOR]

Bacteriophages have shown promise as an alternative to antibiotics for managing or preventing avian pathogenic Escherichia coli (APEC) in the egg industry. In a previous study, a phage cocktail comprising 3 virulent phages was shown to prevent APEC infections in laying hens. The aim of this study was to investigate whether orally and intramuscularly administered phages affect the intestinal barrier function of chickens, with a focus on cecal microbiome. In a 4-d trial, a total of 35 laying hens were randomly assigned to one of four treatment groups: 1) Medium control group (bacterial broth + phage buffer), 2) APEC only control (APEC + buffer); 3) IM group (Phage +APEC), or 4) DW group (phage in drinking water (4 d prior to APEC + APEC). Cecum samples were subjected to 16S rRNA gene sequencing targeting the V4 region to assess the effects of phages on cecal bacterial diversity. A 1-way ANOVA was used to evaluate alpha diversity with respect to treatment and time. Microbial community structure was analyzed using β-dispersion and permutational multivariate analysis of variance (PERMANOVA) to determine the effect of each treatment. Significant (P < 0.05) differentially abundant genera were identified with DESeq2 by fitting a negative binomial model to each treatment vs treatment comparison (“~Treatment”). Across the treatment and control groups, 13 phyla were identified. Firmicutes (53.81%), Bacteroidota (23.83%), Actinobacteriota (1.84%), and Proteobacteria (1.02%) were the most abundant phyla among the amplicon sequence variants (ASVs), with 18.39% being unclassified. Neither richness (P = 0.448) nor Shannon diversity (P = 0.687) exhibited significance in α- diversity metric between treatment and control groups. β-dispersion analysis showed no significant difference (P = 0.239) between treatment and control groups, indicating similar bacterial variability among groups. Moreover, the β-diversity representing microbiota structure was not affected by any phage treatment (P = 0.083). In each treatment group, 76 unique genera were identified, with Megamonas (15.80 %), Lactobacillus (8.76%), Faecalibacterium (7.70 %), Megasphaera (1.58%), Alloprevotella (1.54%), [Ruminococcus] torques group (1.29%), Prevotellaceae UCG-001 (1.14%), Bifidobacterium (1.04%), and Olsenella (0.48%) being the most abundant. Notably, Lactobacillus was more abundant (~ 10 to 20%) in medium control group compared with phage treated and APEC only treatment groups. Furthermore, gene expression profiles of various genera (pairwise) were analyzed using log2 fold change (log2FC), revealing differences (P < 0.05) between control and treatment groups for a total of 58 genera. It was concluded that bacteriophage selectively killed APEC population without comprising the population and structure of cecal microbiome in laying hens. [ABSTRACT FROM AUTHOR]

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100 000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2182 individuals presenting with ataxia and 6658 non-neurological probands recruited in the 100 000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100 000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100 000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci. [ABSTRACT FROM AUTHOR]

Background: Women considering immediate breast reconstruction require high-quality information about the likely need for secondary reconstruction and the long-term risk of revisional surgery to make fully informed decisions about different reconstructive options. Such data are currently lacking. This study aimed to explore the impact of reconstruction type on the number of revisions and secondary reconstructions performed 3, 5, and 8 years after immediate breast reconstruction in a large population-based cohort. Methods: Women undergoing unilateral mastectomy and immediate breast reconstruction for breast cancer or ductal carcinoma in situ in England between 1 April 2009 and 31 March 2015 were identified from National Health Service Hospital Episode Statistics. Numbers of revisions and secondary reconstructions in women undergoing primary definitive immediate breast reconstruction were compared by procedure type at 3, 5, and 8 years after index surgery. Results: Some 16 897 women underwent immediate breast reconstruction with at least 3 years' follow-up. Of these, 14 069 had a definitive reconstruction with an implant only (5193), latissimus dorsi flap with (3110) or without (2373) an implant, or abdominal free flap (3393). Women undergoing implant-only reconstruction were more likely to require revision, with 69.5 per cent (747 of 1075) undergoing at least one revision by 8 years compared with 49.3 per cent (1568 of 3180) in other reconstruction groups. They were also more likely to undergo secondary reconstruction, with the proportion of women having further reconstructive procedures increasing over time: 12.8 per cent (663 of 5193) at 3 years, 14.3 per cent (535 of 3752) at 5 years, and 17.6 per cent (189 of 1075) at 8 years. Conclusion: Long-term rates of revisions and secondary reconstructions were considerably higher after primary implant-based reconstruction than autologous procedures. These results should be shared with patients to support informed decision-making. [ABSTRACT FROM AUTHOR]

Background Changes in adolescents' attitudes towards school are a potential explanation for recent declines in young people's alcohol consumption. However, this has not been tested using multi-national survey data, which would permit stronger causal inferences by ruling out other country-specific explanations. This study, therefore, uses an international survey of schoolchildren to examine the associations between changing attitudes towards school and adolescent alcohol consumption. Methods We used data from 247 325 15-year-olds across 37 countries participating in four waves of the Health Behaviour in School-aged Children study (2001/02–2013/14). Attitudes towards school were assessed using two measures—self-reported pressure from schoolwork and whether respondents like school. Outcome measures were weekly alcohol consumption and having been drunk twice in one's lifetime. We used whole population and gender-specific hierarchical linear probability models to assess the relationship between attitudes and alcohol outcomes within countries over time. Results Country-level changes over time in liking school were not associated with changes in alcohol consumption. However, a 10% increase in feeling pressured by schoolwork was associated with a 1.8% decline in drunkenness [95% confidence interval (CI): −3.2% to −0.3%] and weakly associated with a 1.7% decline in weekly drinking (95% CI: −3.6% to 0.2%). Among girls only, increases in feeling pressured by schoolwork were associated with a 2.1% decline in weekly drinking (95% CI: −3.7% to −0.6%) and a 2.4% decline in drunkenness (95% CI: −3.8% to −1.1%). Conclusion Changes in attitudes towards school may have played a minor role in the decline in alcohol consumption among adolescent girls only. [ABSTRACT FROM AUTHOR]

Linked Comment:M.D. Moncrieff and J.P. Nobes. Br J Dermatol 2021; 185:877. Plain language summary available online [ABSTRACT FROM AUTHOR]

Background: Future innovations in science and technology with an impact on multimodal breast cancer management from a surgical perspective are discussed in this narrative review. The work was undertaken in response to the Commission on the Future of Surgery project initiated by the Royal College of Surgeons of England. Methods: Expert opinion was sought around themes of surgical de-escalation, reduction in treatment morbidities, and improving the accuracy of breast-conserving surgery in terms of margin status. There was emphasis on how the primacy of surgical excision in an era of oncoplastic and reconstructive surgery is increasingly being challenged, with more effective systemic therapies that target residual disease burden, and permit response-adapted approaches to both breast and axillary surgery. Results: Technologies for intraoperative margin assessment can potentially half re-excision rates after breast-conserving surgery, and sentinel lymph node biopsy will become a therapeutic procedure for many patients with node-positive disease treated either with surgery or chemotherapy as the primary modality. Genomic profiling of tumours can aid in the selection of patients for neoadjuvant and adjuvant therapies as well as prevention strategies. Molecular subtypes are predictive of response to induction therapies and reductive approaches to surgery in the breast or axilla. Conclusion: Treatments are increasingly being tailored and based on improved understanding of tumour biology and relevant biomarkers to determine absolute benefit and permit delivery of cost-effective healthcare. Patient involvement is crucial for breast cancer studies to ensure relevance and outcome measures that are objective, meaningful, and patient-centred. [ABSTRACT FROM AUTHOR]

Plain language summary available online [ABSTRACT FROM AUTHOR]

Aims: To describe the temporal trends in Escherichia coli pathotypes and antimicrobial resistance detected in isolates from diseased‐pig cases submitted to the EcL from 2008 to 2016, in Quebec, Canada, and to investigate the presence of spatiotemporal and phylogenetic clusters. Methods and Results: Detection of 12 genes coding for virulence factors in pathogenic E. coli in pigs by PCR and antimicrobial resistance standard disc diffusion assay were performed. Demographic and clinical data were entered in the Animal Pathogenic and Zoonotic E. coli (APZEC) database. ETEC:F4 was the most prevalent pathovirotype among the 3773 cases submitted. The LT:STb:F4 virotype was predominant until 2014, then was overtaken by the LT:STb:STa:F4 virotype. More than 90% of the ETEC:F4 isolates were multidrug resistant. A spatiotemporal cluster of LT:STb:STa:F4 isolates non‐susceptible to enrofloxacin was detected between 4/2015 and 9/2016. Pulsed‐field gel electrophoresis analysis of 137 ETEC:F4 isolates revealed the presence of a cluster composed mainly of LT:STb:STa:F4 isolates non‐susceptible to enrofloxacin. Conclusions: The APZEC database was useful to highlight temporal trends in E. coli pathotypes. A high‐risk ETEC:F4 clone might disseminate in the pig population in Quebec since 2015. Significance and Impact of the Study: Surveillance is crucial to identify new clones and develop control strategies. [ABSTRACT FROM AUTHOR]

The article presents a study designed to examine the practice and short-term outcomes of therapeutic mammaplasty as a treatment method for breast cancer. The authors conclude that therapeutic mammaplasty is a safe and effective treatment method compared to mastectomy or breast-conserving surgery.

Adjuvant radiotherapy in patients with high-risk cutaneous Squamous Cell Carcinoma After surgery (SCC-AFTER): patient and carer views regarding a proposed clinical trial It's certainly worth doing (Patient)If you ... said it [radiotherapy] only benefits thirty percent of patients then there is a school of thought which would say, "Well a hundred percent of patients will want it", and hope that they are in the thirty percent. Dear Editor, Cutaneous squamous cell carcinoma (cSCC) represents the second most common cancer in the UK.1 High-risk cSCC represents a subgroup of this disease with higher risk of metastasis and death,2 and management remains unclear due to a shortage of randomized controlled trials (RCTs).3 We undertook Patient and Public Involvement (PPI) consultations with 13 patients and 3 carers with experience of cSCC, to explore their views about a trial that will investigate effectiveness of treating high-risk cSCC using surgical excision alone compared with surgery plus adjuvant radiotherapy. [Extracted from the article]

Aims To investigate the mechanisms leading to an increase in the prevalence of bla CMY-2 conferring resistance to ceftiofur in pigs receiving a feed medicated with chlortetracycline and penicillin, and to examine the effect of supplementation with a clay mineral on this phenomenon. Methods and Results In 138 bla CMY-2-positive Escherichia coli isolates from faeces of pigs receiving feed supplemented or not with 2% clinoptilolite, from day 2 to day 28 after weaning, isolates from the two groups differed significantly with respect to their phylogenetic group: phylotype A predominated in the supplemented group, whereas phylotypes B1 and D predominated in the control group, as determined by PCR. In 36 representative isolates, pulsed-field gel electrophoresis and antimicrobial susceptibility testing revealed that the bla CMY-2-positive E. coli isolates were polyclonal with diverse antimicrobial resistance patterns and bla CMY-2-carrying plasmids of incompatibility (Inc) groups, A/C, I1 and ColE were observed in transformants as detected by PCR. Enterobacter cloacae possessing bla CMY-2-carrying IncA/C plasmids were found in the pens before introduction of this batch of pigs. The bla CMY-2-positive E. coli isolates were more clonally diverse in the control group than the supplemented group. Conclusions The bla CMY-2 gene appears to have spread both horizontally and clonally in this batch of pigs and may have spread from previous batches of pigs via plasmids carried by Ent. cloacae and expanded in animals of the present batch in the presence of the selection pressure due to administration of chlortetracycline and penicillin in the feed. Feed supplementation may have an effect on clonal diversity of bla CMY-2-positive isolates. Significance and Impact of the Study Implementation of improved hygiene measures, decreased administration of certain antimicrobials on farm and feed supplementation with certain ingredients may limit antimicrobial resistance spread between and within batches of animals. [ABSTRACT FROM AUTHOR]

Feed characteristics may influence the bacterial community composition and metabolic activities in the pig gastrointestinal tract, known to be associated with positive effects on the gut. Use of mash feed is associated with reduced Salmonella excretion, but little is known of its effect on the Escherichia coli population or of the mechanism of action. Our objectives were to assess the effect of feed texture combined with feed particle size on VFA profiles and levels, total E. coli count, and the presence of genes encoding virulence factors of pathogenic E. coli strains in the digestive tract along with their impact on pig performance of fattening pigs. Pigs (n = 840) on a commercial farm received mash or pellet diets of different particle sizes during the fattening period. Caecal and colon contents from 164 pigs were sampled at the slaughterhouse for enumeration of E. coli by quantitative PCR (qPCR) and for VFA quantification by capillary gas chromatography. The yccT gene was used to enumerate total E. coli. Improved pig performances associated with pellet texture and a 500-µm size were observed. Caecal (P = 0.02) and colon (P < 0.01) propionic acid concentrations were lower for pigs receiving pellet rather than mash feed. Similarly, caecal (P = 0.01) and colon (P < 0.001) butyric acid concentrations were also lower for pigs receiving pellet rather than mash feed, as determined by capillary gas chromatography. Moreover, caecal (P = 0.03) and colon (P < 0.001) butyric acid concentrations were higher for pigs receiving a feed with a 1,250-µm particle size rather than a 500-µm particle size. On the other hand, total caecal and colon E. coli levels were higher for pigs receiving pellet feed than for those receiving mash feed. For total E. coli enumeration, caecal (P < 0.01) and colon (P < 0.01) yccT gene copies were higher for pigs receiving pellet rather than mash feed. No effect of particle size on fatty acid concentrations or on E. coli numbers was observed. Virulence gene quantification revealed no trend. Taken together, results showed that mash feed is associated with lower growth performance but with favorable intestinal changes linked to VFA levels and E. coli reduction in the intestine. [ABSTRACT FROM AUTHOR]

Many surveys of respondents from multiple countries or subnational regions have now been fielded on multiple occasions. Social scientists are regularly using multilevel models to analyse the data generated by such surveys, investigating variation across both space and time. We show, however, that such models are usually specified erroneously. They typically omit one or more relevant random effects, thereby ignoring important clustering in the data, which leads to downward biases in the standard errors. These biases occur even if the fixed effects are specified correctly; if the fixed effects are incorrect, erroneous specification of the random effects worsens biases in the coefficients. We illustrate these problems using Monte Carlo simulations and two empirical examples. Our recommendation to researchers fitting multilevel models to comparative longitudinal survey data is to include random effects at all potentially relevant levels, thereby avoiding any mismatch between the random and fixed parts of their models. [ABSTRACT FROM AUTHOR]

Summary: Most pre-mRNA transcripts in eukaryotic cells must undergo splicing to remove introns and join exons, and splicing elements present a large mutational target for disease-causing mutations. Splicing elements are strongly position dependent with respect to the transcript annotations. In 2012, we presented Spliceman, an online tool that used positional dependence to predict how likely distant mutations around annotated splice sites were to disrupt splicing. Here, we present an improved version of the previous tool that will be more useful for predicting the likelihood of splicing mutations. We have added industry-standard input options (i.e. Spliceman now accepts variant call format files), which allow much larger inputs than previously available. The tool also can visualize the locations--within exons and introns--of sequence variants to be analyzed and the predicted effects on splicing of the pre-mRNA transcript. In addition, Spliceman2 integrates with RNAcompete motif libraries to provide a prediction of which trans-acting factors binding sites are disrupted/created and links out to the UCSC genome browser. In summary, the new features in Spliceman2 will allow scientists and physicians to better understand the effects of single nucleotide variations on splicing. [ABSTRACT FROM AUTHOR]

What makes people concerned about environmental degradation and willing to pay for its prevention? Recent survey research argues that richer people are greener—that residents of more economically developed countries, as well as relatively wealthier people within countries, are more concerned about the state of the natural environment and more willing to pay to protect it. This article questions this view, using survey data on multiple distinct aspects of environmental concern, from a larger sample of countries, and, where possible, taking into account not just cross-sectional differences among nations but also change over time. The analyses reported in this article show that environmental concern is generally higher in poorer countries, and there is no relationship over time between economic development and people’s willingness to pay for environmental protection. Within countries, richer people are slightly more concerned about the environment, but only on some dimensions and not others. [ABSTRACT FROM PUBLISHER]

Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising inflammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after iv dose administration once every 2 weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic inflammatory response, and hepatic injury. Laboratory findings included elevated plasma cytokines, an inflammatory leukogram, and increased liver transaminases with histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues; a toxicology profile consistent with TNF-α-mediated toxicity. Dogs exhibited more severe findings than rats, and humans did not exhibit these findings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum monocyte chemoattractant protein-1, and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers. [ABSTRACT FROM PUBLISHER]

Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a potent and selective IAP antagonist being developed as an anticancer agent. In preclinical safety studies, dogs were particularly sensitive to GDC-0152 showing adverse signs of a tumor necrosis factor alpha (TNF-α) driven systemic inflammatory response, related to cellular IAP degradation and activation of NFκB signaling, at lower exposures compared with rat. In addition, downstream increases in systemic levels of cytokines and chemokines, such as monocyte chemotactic protein-1 (MCP-1), were observed. A semimechanistic population toxicokinetic/toxicodynamic (TK/TD) model incorporating transit compartments was used to fit MCP-1 plasma concentrations from rats or dogs given iv GDC-0152 doses. Estimated TD parameters inferred that lower GDC-0152 plasma concentrations triggered more severe increases in plasma MCP-1 in dogs compared with rats. Human simulations performed using dog TD parameters and human pharmacokinetics predicted 300–2400% increases of MCP-1 in humans at iv doses from 0.76 to 1.48mg/kg. Similar simulations using rat TD parameters suggest little or no change. Patients given iv doses of GDC-0152 up to 1.48mg/kg iv showed no substantial increases in systemic MCP-1 or signs of a severe TNF-α driven systemic inflammatory response. Emerging clinical data reported for other IAP antagonists are consistent with our observations. Taken together, the data suggest dogs are more sensitive to IAP antagonists compared with humans and rats. This study illustrates how TK/TD analysis can be utilized to quantitatively translate and context an identified preclinical safety risk in dogs to humans. [ABSTRACT FROM AUTHOR]

In this study, the influence of the probiotics, Pediococcus acidilactici (PA) and Saccharomyces cerevisiae boulardii (SCB), on intestinal immune traits and resistance to enterotoxigenic Escherichia coli (ETEC) infection was evaluated in pigs. Two weeks before farrowing, 30 sows and their future litters were allocated to the following treatments: 1) control group without antibiotic or probiotic treatment (CTRL), 2) control with antibiotic (tiamulin) added to weanling feed (ABT), or litters treated with 3) PA, 4) SCB, or 5) PA+SCB from 24 h after birth. During lactation, PA, SCB, or PA+SCB were given to piglets 3 times a week by gavage. After weaning at 21 d of age, probiotics or ABT were added to the diet. Four pigs per litter were chosen to evaluate performance and blood concentrations of folic acid and vitamin B12. Three of these were orally challenged with an ETEC strain on d 49 to 51 and killed on d 52. Three piglets from the rest of the litter were slaughtered on d 18 and 3 others on d 24. Blood, ileum, and mesenteric lymph node (MLN) samples were taken to characterize leukocyte populations, determine IgA concentrations in ileal flushes, and evaluate bacterial translocation in MLN. No treatment effect on postweaning performance and on blood concentrations of folic acid and vitamin B12 was observed. In the ileum, the percentage of CD4-CD8+low T cells was greater (P = 0.05) in 18-d-old nursed piglets treated with PA than in those of the CTRL and PA+SCB groups. In the MLN, the percentage of CD8+ T cells was not affected by any of the treatments at d 18 and 24 but decreased (P = 0.006) after weaning. In the blood, CD8+ T cells were not affected by treatments or weaning. After the ETEC challenge (d 52), bacterial translocation to MLN was reduced (P = 0.05) in pigs treated with PA, SCB, PA+SCB, or ABT compared with CTRL. No treatment effect was observed on blood leukocyte populations after ETEC challenge, although a time effect (d 42 vs. 52) indicated that blood CD4+ and γδ-T lymphocytes were increased (P < 0.05) on d 52 compared with d 42, whereas CD4-CD8+lowT lymphocytes and monocytes were markedly reduced (P < 0.01). Finally, the IgA concentration in ileal flushes collected on d 42 and 52 was greater in SCB and CTRL piglets than in ABT and PA piglets. In conclusion, probiotics may have the potential to modulate establishment of lymphocyte populations and IgA secretion in the gut and to reduce bacterial translocation to MLN after ETEC infection. [ABSTRACT FROM AUTHOR]

The article investigates the association between leptin receptor genotype at Gln223Arg with body composition, bone mineral density (BMD) and vertebral fracture in postmenopausal Danish women. The study uses a population-based study of 1430 women, wherein three well-known non-synonymous leptin receptor (LEPR) single nucleotide polymorphisms (SNPs) were genotyped for qualitative and quantitative association analysis. The results of the study were discussed.

Using a porcine ileal in vitro organ culture model, we have demonstrated that egg yolk-derived antibodies specific for the attaching and effacing Escherichia coli (AEEC) virulence factors intimin and translocated intimin receptor (Tir), but not those specific for the AEEC-secreted proteins EspA, EspB and EspD, significantly reduced the bacterial adherence of the porcine enteropathogenic E. coli strain ECL1001, formerly 86-1390. Moreover, antibodies specific for intimin and Tir also significantly reduced bacterial adherence of heterologous AEEC strains, including human, bovine and canine enteropathogenic E. coli strains, as well as of O157:H7 Shiga toxin-producing E. coli strains in this model. In addition, we demonstrated that the oral administration of these anti-intimin antibodies significantly reduced the extent of attaching and effacing lesions found in the small intestine of weaned pigs challenged with the porcine enteropathogenic E. coli strain ECL1001. Overall, our results underline the potential use of specific egg yolk-derived antibodies as a novel approach for the prevention of AEEC infections. [ABSTRACT FROM AUTHOR]

Background: Reducing inequalities in health is an enduring global public health challenge. Worryingly in England, inequalities across some groups and places are worsening, highlighted and exacerbated by the Covid-19 pandemic. While there has been growing interest in exploring public understandings of health inequalities, few studies have explored the views of young people. Our study seeks to redress this by exploring young people's perspectives of inequalities in health. Methods: Working with existing youth organisations, we recruited young people (aged 13-21) from six youth groups in areas of high deprivation across three geographical locations in England. Each group took part in three interlinked focus groups (n = 18), the majority of which were run online using video conferencing platforms. Focus groups were co-delivered with partnering youth organisations during 2021. They involved participatory concept mapping activities, and the discussion of health related news articles. Results: Key themes emerged around young people's perspectives of: i) factors influencing health within their local area; ii) understandings of inequalities in health; and iii) key messages to convey to those with a role in addressing health inequalities at a place level. Conclusions: Our study highlights the importance of exploring and understanding young people's perspectives of inequalities in order to better shape policies which are supported by the communities and people they impact. Key messages: Young people have a nuanced, experiential understanding of key factors influencing their health and inequalities in health within their local areas. Building upon young people's understandings of inequalities in health provides opportunities to mobilise support for policies seeking to change the distribution of key social determinants. [ABSTRACT FROM AUTHOR]