Development and Characterisation of Polymeric Nanacapsules Containing Macromolecule

Oral drug delivery systems are the most common route of administration. However, development oral delivery system containing macromolecules is still challenging due to different hurdles, including, digestive enzymes degradation and physiochemical properties of the molecules. Currently, several techniques have been applied to deliver the macromolecules orally e.g. polymer conjugates, excipients such as cyclodextrin, and entrapment inside carriers, such as liposomes, and nanocapsule systems. Accordingly, the aim of this study is to overcome these challenges by encapsulating macromolecule inside polymeric nanocapsules, trypsin as a protein was used as a model macromolecule

Strand selective generation of endo-siRNAs from the Na/phosphate transporter gene Slc34a1 in murine tissues

Natural antisense transcripts (NATs) are important regulators of gene expression. Recently, a link between antisense transcription and the formation of endo-siRNAs has emerged. We investigated the bi-directionally transcribed Na/phosphate cotransporter gene (Slc34a1) under the aspect of endo-siRNA processing. Mouse Slc34a1 produces an antisense transcript that represents an alternative splice product of the Pfn3 gene located downstream of Slc34a1. The antisense transcript is prominently found in testis and in kidney. Co-expression of in vitro synthesized sense/antisense transcripts in Xenopus oocytes indicated processing of the overlapping transcripts into endo-siRNAs in the nucleus. Truncation experiments revealed that an overlap of at least 29 base-pairs is required to induce processing. We detected endo-siRNAs in mouse tissues that co express Slc34a1 sense/antisense transcripts by northern blotting. The orientation of endo-siRNAs was tissue specific in mouse kidney and testis. In kidney where the Na/phosphate cotransporter fulfils its physiological function endo-siRNAs complementary to the NAT were detected, in testis both orientations were found. Considering the wide spread expression of NATs and the gene silencing potential of endo-siRNAs we hypothesized a genome-wide link between antisense transcription and monoallelic expression. Significant correlation between random imprinting and antisense transcription could indeed be established. Our findings suggest a novel, more general role for NATs in gene regulation

Planar localisation analyses: a novel application of a centre of mass approach

Sound localisation is one of the key roles for listening, and measuring localisation performance is a mainstay of the hearing research laboratory. Such measurements consider both accuracy and, for incorrect trials, the size of the error. In terms of error analysis, localisation studies have frequently used general univariate techniques in conjunction with either mean signed or unsigned error measurements. This approach can make inappropriate distributional assumptions and so more suitable alternatives based on directional statistics (e.g. based on von Mises distributed data) have also been used. However these are not readily computed using most commercially available, commonly used statistical software, and are generally only defined for simple experimental designs. We describe a novel use of a 'centre of mass' approach for describing localisation data jointly in terms of accuracy and size of error. This spatial method offers powerful, yet flexible, statistical analysis using standard multivariate analysis of variance (MANOVA)

Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae

Streptococcus pneumoniae is a major human pathogen that can cause severe invasive diseases such as pneumonia, septicaemia and meningitis. Young children are at a particularly high risk, with an estimated 3–4 million cases of severe disease and between 300 000 and 500 000 deaths attributable to pneumococcal disease each year. The haemolytic toxin pneumolysin (Ply) is a primary virulence factor for this bacterium, yet despite its key role in pathogenesis, immune evasion and transmission, the regulation of Ply production is not well defined. Using a genome-wide association approach, we identified a large number of potential affectors of Ply activity, including a gene acquired horizontally on the antibiotic resistance-conferring Integrative and Conjugative Element (ICE) ICESp23FST81. This gene encodes a novel modular protein, ZomB, which has an N-terminal UvrD-like helicase domain followed by two Cas4-like domains with potent ATP-dependent nuclease activity. We found the regulatory effect of ZomB to be specific for the ply operon, potentially mediated by its high affinity for the BOX repeats encoded therein. Using a murine model of pneumococcal colonization, we further demonstrate that a ZomB mutant strain colonizes both the upper respiratory tract and lungs at higher levels when compared to the wild-type strain. While the antibiotic resistance-conferring aspects of ICESp23FST81 are often credited with contributing to the success of the S. pneumoniae lineages that acquire it, its ability to control the expression of a major virulence factor implicated in bacterial transmission is also likely to have played an important role

Sticky knowledge: A possible model for investigating implementation in healthcare contexts

<p>Abstract</p> <p>Background</p> <p>In health care, a well recognized gap exists between what we know should be done based on accumulated evidence and what we actually do in practice. A body of empirical literature shows organizations, like individuals, are difficult to change. In the business literature, knowledge management and transfer has become an established area of theory and practice, whilst in healthcare it is only starting to establish a firm footing. Knowledge has become a business resource, and knowledge management theorists and practitioners have examined how knowledge moves in organisations, how it is shared, and how the return on knowledge capital can be maximised to create competitive advantage. New models are being considered, and we wanted to explore the applicability of one of these conceptual models to the implementation of evidence-based practice in healthcare systems.</p> <p>Methods</p> <p>The application of a conceptual model called sticky knowledge, based on an integration of communication theory and knowledge transfer milestones, into a scenario of attempting knowledge transfer in primary care.</p> <p>Results</p> <p>We describe Szulanski's model, the empirical work he conducted, and illustrate its potential applicability with a hypothetical healthcare example based on improving palliative care services. We follow a doctor through two different posts and analyse aspects of knowledge transfer in different primary care settings. The factors included in the sticky knowledge model include: causal ambiguity, unproven knowledge, motivation of source, credibility of source, recipient motivation, recipient absorptive capacity, recipient retentive capacity, barren organisational context, and arduous relationship between source and recipient. We found that we could apply all these factors to the difficulty of implementing new knowledge into practice in primary care settings.</p> <p>Discussion</p> <p>Szulanski argues that knowledge factors play a greater role in the success or failure of a knowledge transfer than has been suspected, and we consider that this conjecture requires further empirical work in healthcare settings.</p

Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study

Background: Long COVID, characterised by various symptoms and complications, potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. Objective: This study aims to assess the healthcare utilisation of individuals with long COVID. Methods: With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A[and]E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. Results: We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.07, 95% CI: 7.54 – 8.64), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.47 – 1.50). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58 - 29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73 - 16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.47, 95% CI = 7.02 – 7.95), with costs being 43% higher than the comparator group (cost ratio = 1.43, 95% CI: 1.38 – 1.49). The long COVID group costs approximately £2,500 per person per year (predicted mean cost: £2,562.50, 95% CI: £2,335.60 - £2,819.22), and the comparator group costs £1,500 (predicted mean cost: £1,527.43, 95% CI: £1,404.33 - 1,664.45.) Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. Conclusion: Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID

Cohort profile: OpenPROMPT

OpenPROMPT is a cohort of individuals with longitudinal patient reported questionnaire data and linked to routinely collected health data from primary and secondary care. Data were collected between November 2022 and October 2023 in England. OpenPROMPT was designed to measure the impact of long COVID on health-related quality-of-life (HRQoL). With the approval of NHS England we collected responses from 7,574 individuals, with detailed questionnaire responses from 6,337 individuals who responded using a smartphone app. Data were collected from each participant over 90 days at 30-day intervals using questionnaires to ask about HRQoL, productivity and symptoms of long COVID. Responses from the majority of OpenPROMPT (6,006; 79.3%) were linked to participants’ existing health records from primary care, secondary care, COVID-19 testing and vaccination data. Analysis takes place using the OpenSAFELY data analysis platform which provides a secure software interface allowing the analysis of pseudonymized primary care patient records from England. OpenPROMPT can currently be used to estimate the impact of long COVID on HRQoL, and because of the linkage within OpenSAFELY, the data from OpenPROMPT can be used to enrich routinely collected records in further research by approved researchers on behalf of NHS England

Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study.

BACKGROUND: Long COVID potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. METHODS: This study aims to assess the healthcare utilisation of individuals with long COVID. With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. RESULTS: We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.29, 95% CI: 7.74-8.87), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.48-1.51). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58-29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73-16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.66, 95% CI = 7.20-8.15), with costs being 44% higher than the comparator group (cost ratio = 1.44, 95% CI: 1.39-1.50). The long COVID group costs approximately £2500 per person per year (predicted mean cost: £2562.50, 95% CI: £2335.60-£2819.22), and the comparator group costs £1500 (predicted mean cost: £1527.43, 95% CI: £1404.33-1664.45). Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. CONCLUSIONS: Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID

Meiotic nuclear divisions in budding yeast require PP2ACdc55-mediated antagonism of Net1 phosphorylation by Cdk

During meiosis, one round of deoxyribonucleic acid replication is followed by two rounds of nuclear division. In Saccharomyces cerevisiae, activation of the Cdc14 early anaphase release (FEAR) network is required for exit from meiosis I but does not lead to the activation of origins of replication. The precise mechanism of how FEAR regulates meiosis is not understood. In this paper, we report that premature activation of FEAR during meiosis caused by loss of protein phosphatase PP2ACdc55 activity blocks bipolar spindle assembly and nuclear divisions. In cdc55 meiotic null (cdc55-mn) cells, the cyclin-dependent kinase (Cdk)–counteracting phosphatase Cdc14 was released prematurely from the nucleolus concomitant with hyperphosphorylation of its nucleolar anchor protein Net1. Crucially, a mutant form of Net1 that lacks six Cdk phosphorylation sites rescued the meiotic defect of cdc55-mn cells. Expression of a dominant mutant allele of CDC14 mimicked the cdc55-mn phenotype. We propose that phosphoregulation of Net1 by PP2ACdc55 is essential for preventing precocious exit from meiosis I

Global assessment of marine plastic exposure risk for oceanic birds

Plastic pollution is distributed patchily around the world's oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species