Variation in harms and benefits of prostate-specific antigen screening for prostate cancer by socio-clinical risk factors: A rapid review.

Objective: To analyse the latest evidence on the relative harms and benefits of screening and diagnostic pathways with close examination of (i) men aged 50 years or older, (ii) men whose ethnicity places them at higher risk and (iii) men with a family history. Methods: We conducted a literature search using PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases and other sources, from January 1990 to 25 January 2023. Two independent reviewers selected for randomised controlled trials (RCTs) and cohort studies which met our inclusion criteria. Results: Twenty-eight articles were selected, from six trials, including the Göteborg trial-reported separately from European Randomised Study of Screening for Prostate Cancer (ERSPC). Prostate-specific antigen (PSA)-based screening led to the increased detection of low-grade cancer and reduction of advanced/metastatic disease but had contradictory effects on prostate cancer (PCa)-specific mortality (no difference or reduced), possibly due to issues of contamination or compliance. Screening men from a relatively young age (50-55) reduced risk of PCa-specific mortality in a subanalysis of an 18-year follow-up study and in a 17-year cohort study from the main Göteborg trial. Moreover, one Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial analysis reported a trend of reduced risk of PCa-specific mortality for men with a family history who were screened. [Correction added on 05 March 2024, after first online publication: "Cancer Screening Trial" has been added to the preceding sentence.] However, we did not find relevant studies for ethnicity. Conclusion: Under current UK practice, the choice to conduct a PSA test relies on a shared decision-making approach guided by known risk factors. However, we found there was a lack of strong evidence on the harms and benefits of PSA screening by socio-clinical risk factors and suggest further research is required to understand the long-term impact of screening on high-risk populations in the current diagnostic setting.

The impact of pre-biopsy MRI and additional testing on prostate cancer screening outcomes: A rapid review.

Objective: This work aims to examine the latest evidence on the impact of pre-biopsy MRI, in addition to prostate-specific antigen (PSA) testing, on health outcomes and quality of life. Methods: We conducted a literature search including PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases, with a limited scan of (i) guidelines and (ii) references from trial reports, from January 2005 to 25th January 2023. Two independent reviewers selected randomised controlled trials (RCT) and cohort studies which met our inclusion criteria. Results: One hundred thirty-seven articles were identified, and seven trial articles were selected. Trial interventions were as follows: (i) PSA blood test, (ii) additional tests such as pre-biopsy multiparametric magnetic resonance imaging (mpMRI) and Biparametric MRI (bpMRI), and (iii) MRI targeted biopsy and standard biopsy. Compared with standard biopsy, MRI-based interventions led to increased detection of clinically significant cancers in three studies and decreased detection of clinically insignificant cancer (Gleason grade 3 + 3) in four studies. However, PROstate Magnetic resonance Imaging Study (PROMIS) and Stockholm3 with MRI (STHLM3-MRI) studies reported different trends depending on the scenario studied in PROMIS (MRI triage and MRI directed biopsy vs. MRI triage and standard biopsy) and thresholds used in STHLM3-MRI (≥0·11 and ≥0·15). MRI also helped 8%-49% of men avoid biopsy, in six out of seven studies, but not in STHLM3-MRI at ≥0.11. Interestingly, the proportion of men who experienced sepsis and UTI was low across studies. Conclusion: This review found that a combination of approaches, centred on the use of pre-biopsy MRI, may improve the detection of clinically significant cancers and reduce (i) the diagnosis of clinically insignificant cancers and (ii) unnecessary biopsies, compared with PSA testing and standard biopsy alone. However, the impact of such interventions on longer term outcomes such as prostate cancer-specific mortality has not yet been assessed.

Economic evaluation of population-based, expanded reproductive carrier screening for genetic diseases in Australia.

PURPOSE: This study aimed to evaluate the cost effectiveness of population-based, expanded reproductive carrier screening (RCS) for a 300 recessive gene panel from health service and societal perspectives. METHODS: A microsimulation model (PreConMod) was developed using 2016 Australian Census data as the base population. Epidemiologic, health, and indirect cost data were based on literature review. The study assessed the incremental cost effectiveness ratio of expanded RCS compared with (1) no population screening and (2) 3-condition screening for cystic fibrosis, spinal muscular atrophy, and fragile X syndrome in a single birth cohort. Averted affected births and health service savings with expanded RCS were projected to year 2061. Both one-way and probability sensitivity analyses were conducted to assess the uncertainty of the parameter inputs. RESULTS: Expanded RCS was cost saving compared with no population screening and cost effective compared with the 3-condition screening (incremental cost effectiveness ratio of Australian dollar [AUD] 6287 per quality-adjusted life year gained) at an uptake rate of 50% for RCS, 59% for in vitro fertilization and preimplantation genetic testing, 90% for prenatal diagnosis testing, and 50% for elective termination of affected pregnancies and a cost of AUD595 per couple screened. Our model predicts that expanded RCS would avert one-third of affected births in a single birth cohort and reduce lifetime health service spending by AUD632.0 million. Expanded RCS was estimated to be cost saving from the societal perspective. CONCLUSION: Expanded RCS is cost effective from health service and societal perspectives. Expanded RCS is projected to avert significantly more affected births and result in health service saving beyond those expected from 3-condition screening or no population screening.

High-Speed Infrared Radiation Thermometer for the Investigation of Early Stage Explosive Development and Fireball Expansion.

The understanding of blast loads is critical for the development of infrastructure that protects against explosions. However, the lack of high-quality experimental work on the characterisation of such loads prevents a better understanding of many scenarios. Blast loads are typically characterised by use of some form of pressure gauge, from which the temperature can be inferred from a pressure measurement. However, such an approach to temperature measurement is limited; it assumes ideal gas laws apply throughout, which may not be the case for high temperature and pressure scenarios. In contrast, infrared radiation thermometers (IRTs) perform a measurement of temperature based upon the emitted radiance from the target object. The IRTs can measure fast changes in transient temperature, making them seemingly ideal for the measurement of a fireball's temperature. In this work, we present the use of a high-speed IRT for the measurement of early-stage explosive development and fireball expansion within a confined blast, with the temperature of the explosive fireball measured from its emitted radiance. The temperature measured by the IRT was corroborated against the temperature inferred from a pressure gauge measurement; both instruments measured the same temperature from the quasi-static pressure (QSP) point onwards. Before the QSP point, it is deduced that the IRT measures the average temperature of the fireball over a wide field-of-view (FOV), as opposed to that inferred from the singular shocks detected by the pressure gauge. Therefore, use of an IRT, in tandem with a pressure gauge, provides a potential invaluable measurement technique for the characterisation the early stages of a fireball as it develops and expands.

A systematic review of the validity, reliability, and feasibility of measurement tools used to assess the physical activity and sedentary behaviour of pre-school aged children.

Physical activity (PA) and sedentary behaviour (SB) of pre-school aged children are associated with important health and developmental outcomes. Accurate measurement of these behaviours in young children is critical for research and practice in this area. The aim of this review was to examine the validity, reliability, and feasibility of measurement tools used to assess PA and SB of pre-school aged children.Searches of electronic databases, and manual searching, were conducted to identify articles that examined the measurement properties (validity, reliability or feasibility) of measurement tools used to examine PA and/or SB of pre-school aged children (3-7 years old). Following screening, data were extracted and risk of bias assessment completed on all included articles.A total of 69 articles, describing 75 individual studies were included. Studies assessed measurement tools for PA (n = 27), SB (n = 5), and both PA and SB (n = 43). Outcome measures of PA and SB differed between studies (e.g. moderate to vigorous activity, step count, posture allocation). Most studies examined the measurement properties of one measurement tool only (n = 65). Measurement tools examined included: calorimetry, direct observation, combined heart rate and accelerometry, heart rate monitors, accelerometers, pedometers, and proxy report (parent, carer or teacher reported) measures (questionnaires or diaries). Studies most frequently assessed the validity (criterion and convergent) (n = 65), face and content validity (n = 2), test-retest reliability (n = 10) and intra-instrument reliability (n = 1) of the measurement tools. Feasibility data was abstracted from 41 studies.Multiple measurement tools used to measure PA and SB in pre-school aged children showed some degree of validity, reliability and feasibility, but often for different purposes. Accelerometers, including the Actigraph (in particular GT3X versions), Actical, ActivPAL and Fitbit (Flex and Zip), and proxy reported measurement tools used in combination may be useful for a range of outcome measures, to measure intensity alongside contextual information.

New Hope for a "Cursed" Crop? Understanding Stakeholder Attitudes to Plant Molecular Farming With Modified Tobacco in Europe.

Plant molecular farming (PMF) with tobacco could provide a sustainable and cheap platform for the production of high-value proteins for medical use. It could also offer European tobacco farmers an alternative, healthful end use for their crop. New plant breeding techniques (NPBTs) offer a means of quickly and precisely optimizing molecular farming platforms for this purpose. However, there has been little empirical research focussing on the barriers and facilitators of these technologies in the agricultural sphere. Here, we explore key stakeholder perceptions toward this combination of technologies, exploring their understanding of risk and opportunity. We interviewed N = 24 key stakeholders - tobacco farmers, agronomists, policymakers, and researchers - in three tobacco-growing areas of Spain and Italy. Our findings demonstrate these stakeholders have a favorable attitude toward PMF with tobacco due to its beneficial medical purpose and the opportunity it provides farmers to continue growing tobacco in a declining European market. Tobacco producers also reported favorable views toward NPBTs, though for some this was contingent on their use for non-food crops like tobacco. Most stakeholders' concerns are economic in nature, such as potential profitability and demands for new agronomic practices or infrastructure. Tobacco producer associations were thought to be important facilitators for future PMF scale-up. The attitude toward these technologies by smoking tobacco companies is, however, unknown and constitutes a potential risk to the development of PMF.

Shotguns vs Lasers: Identifying barriers and facilitators to scaling-up plant molecular farming for high-value health products.

Plant molecular farming (PMF) is a convenient and cost-effective way to produce high-value recombinant proteins that can be used in the production of a range of health products, from pharmaceutical therapeutics to cosmetic products. New plant breeding techniques (NPBTs) provide a means to enhance PMF systems more quickly and with greater precision than ever before. However, the feasibility, regulatory standing and social acceptability of both PMF and NPBTs are in question. This paper explores the perceptions of key stakeholders on two European Union (EU) Horizon 2020 programmes-Pharma-Factory and Newcotiana-towards the barriers and facilitators of PMF and NPBTs in Europe. One-on-one qualitative interviews were undertaken with N = 20 individuals involved in one or both of the two projects at 16 institutions in seven countries (Belgium, France, Germany, Italy, Israel, Spain and the UK). The findings indicate that the current EU regulatory environment and the perception of the public towards biotechnology are seen as the main barriers to scaling-up PMF and NPBTs. Competition from existing systems and the lack of plant-specific regulations likewise present challenges for PMF developing beyond its current niche. However, respondents felt that the communication of the benefits and purpose of NPBT PMF could provide a platform for improving the social acceptance of genetic modification. The importance of the media in this process was highlighted. This article also uses the multi-level perspective to explore the ways in which NPBTs are being legitimated by interested parties and the systemic factors that have shaped and are continuing to shape the development of PMF in Europe.

Long-read genome sequence assembly provides insight into ongoing retroviral invasion of the koala germline.

The koala retrovirus (KoRV) is implicated in several diseases affecting the koala (Phascolarctos cinereus). KoRV provirus can be present in the genome of koalas as an endogenous retrovirus (present in all cells via germline integration) or as exogenous retrovirus responsible for somatic integrations of proviral KoRV (present in a limited number of cells). This ongoing invasion of the koala germline by KoRV provides a powerful opportunity to assess the viral strategies used by KoRV in an individual. Analysis of a high-quality genome sequence of a single koala revealed 133 KoRV integration sites. Most integrations contain full-length, endogenous provirus; KoRV-A subtype. The second most frequent integrations contain an endogenous recombinant element (recKoRV) in which most of the KoRV protein-coding region has been replaced with an ancient, endogenous retroelement. A third set of integrations, with very low sequence coverage, may represent somatic cell integrations of KoRV-A, KoRV-B and two recently designated additional subgroups, KoRV-D and KoRV-E. KoRV-D and KoRV-E are missing several genes required for viral processing, suggesting they have been transmitted as defective viruses. Our results represent the first comprehensive analyses of KoRV integration and variation in a single animal and provide further insights into the process of retroviral-host species interactions.

Infection with koala retrovirus subgroup B (KoRV-B), but not KoRV-A, is associated with chlamydial disease in free-ranging koalas (Phascolarctos cinereus).

The virulence of chlamydial infection in wild koalas is highly variable between individuals. Some koalas can be infected (PCR positive) with Chlamydia for long periods but remain asymptomatic, whereas others develop clinical disease. Chlamydia in the koala has traditionally been studied without regard to coinfection with other pathogens, although koalas are usually subject to infection with koala retrovirus (KoRV). Retroviruses can be immunosuppressive, and there is evidence of an immunosuppressive effect of KoRV in vitro. Originally thought to be a single endogenous strain, a new, potentially more virulent exogenous variant (KoRV-B) was recently reported. We hypothesized that KoRV-B might significantly alter chlamydial disease outcomes in koalas, presumably via immunosuppression. By studying sub-groups of Chlamydia and KoRV infected koalas in the wild, we found that neither total KoRV load (either viraemia or proviral copies per genome), nor chlamydial infection level or strain type, was significantly associated with chlamydial disease risk. However, PCR positivity with KoRV-B was significantly associated with chlamydial disease in koalas (p = 0.02961). This represents an example of a recently evolved virus variant that may be predisposing its host (the koala) to overt clinical disease when co-infected with an otherwise asymptomatic bacterial pathogen (Chlamydia).

A transcriptome resource for the koala (Phascolarctos cinereus): insights into koala retrovirus transcription and sequence diversity.

BACKGROUND: The koala, Phascolarctos cinereus, is a biologically unique and evolutionarily distinct Australian arboreal marsupial. The goal of this study was to sequence the transcriptome from several tissues of two geographically separate koalas, and to create the first comprehensive catalog of annotated transcripts for this species, enabling detailed analysis of the unique attributes of this threatened native marsupial, including infection by the koala retrovirus. RESULTS: RNA-Seq data was generated from a range of tissues from one male and one female koala and assembled de novo into transcripts using Velvet-Oases. Transcript abundance in each tissue was estimated. Transcripts were searched for likely protein-coding regions and a non-redundant set of 117,563 putative protein sequences was produced. In similarity searches there were 84,907 (72%) sequences that aligned to at least one sequence in the NCBI nr protein database. The best alignments were to sequences from other marsupials. After applying a reciprocal best hit requirement of koala sequences to those from tammar wallaby, Tasmanian devil and the gray short-tailed opossum, we estimate that our transcriptome dataset represents approximately 15,000 koala genes. The marsupial alignment information was used to look for potential gene duplications and we report evidence for copy number expansion of the alpha amylase gene, and of an aldehyde reductase gene.Koala retrovirus (KoRV) transcripts were detected in the transcriptomes. These were analysed in detail and the structure of the spliced envelope gene transcript was determined. There was appreciable sequence diversity within KoRV, with 233 sites in the KoRV genome showing small insertions/deletions or single nucleotide polymorphisms. Both koalas had sequences from the KoRV-A subtype, but the male koala transcriptome has, in addition, sequences more closely related to the KoRV-B subtype. This is the first report of a KoRV-B-like sequence in a wild population. CONCLUSIONS: This transcriptomic dataset is a useful resource for molecular genetic studies of the koala, for evolutionary genetic studies of marsupials, for validation and annotation of the koala genome sequence, and for investigation of koala retrovirus. Annotated transcripts can be browsed and queried at http://koalagenome.org.

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes.

BACKGROUND: About forty human diseases are caused by repeat instability mutations. A distinct subset of these diseases is the result of extreme expansions of polymorphic trinucleotide repeats; typically CAG repeats encoding poly-glutamine (poly-Q) tracts in proteins. Polymorphic repeat length variation is also apparent in human poly-Q encoding genes from normal individuals. As these coding sequence repeats are subject to selection in mammals, it has been suggested that normal variations in some of these typically highly conserved genes are implicated in morphological differences between species and phenotypic variations within species. At present, poly-Q encoding genes in non-human mammalian species are poorly documented, as are their functions and propensities for polymorphic variation. RESULTS: The current investigation identified 178 bovine poly-Q encoding genes (Q ≥ 5) and within this group, 26 genes with orthologs in both human and mouse that did not contain poly-Q repeats. The bovine poly-Q encoding genes typically had ubiquitous expression patterns although there was bias towards expression in epithelia, brain and testes. They were also characterised by unusually large sizes. Analysis of gene ontology terms revealed that the encoded proteins were strongly enriched for functions associated with transcriptional regulation and many contributed to physical interaction networks in the nucleus where they presumably act cooperatively in transcriptional regulatory complexes. In addition, the coding sequence CAG repeats in some bovine genes impacted mRNA splicing thereby generating unusual transcriptional diversity, which in at least one instance was tissue-specific. The poly-Q encoding genes were prioritised using multiple criteria for their likelihood of being polymorphic and then the highest ranking group was experimentally tested for polymorphic variation within a cattle diversity panel. Extensive and meiotically stable variation was identified. CONCLUSIONS: Transcriptional diversity can potentially be generated in poly-Q encoding genes by the impact of CAG repeat tracts on mRNA alternative splicing. This effect, combined with the physical interactions of the encoded proteins in large transcriptional regulatory complexes suggests that polymorphic variations of proteins in these complexes have strong potential to affect phenotype.

Characterization of a complex chemosensory signal transduction system which controls twitching motility in Pseudomonas aeruginosa.

Virulence of the opportunistic pathogen Pseudomonas aeruginosa involves the coordinate expression of a wide range of virulence factors including type IV pili which are required for colonization of host tissues and are associated with a form of surface translocation termed twitching motility. Twitching motility in P. aeruginosa is controlled by a complex signal transduction pathway which shares many modules in common with chemosensory systems controlling flagella rotation in bacteria and which is composed, in part, of the previously described proteins PilG, PilH, PilI, PilJ and PilK. Here we describe another three components of this pathway: ChpA, ChpB and ChpC, as well as two downstream genes, ChpD and ChpE, which may also be involved. The central component of the pathway, ChpA, possesses nine potential sites of phosphorylation: six histidine-containing phosphotransfer (HPt) domains, two novel serine- and threonine-containing phosphotransfer (SPt, TPt) domains and a CheY-like receiver domain at its C-terminus, and as such represents one of the most complex signalling proteins yet described in nature. We show that the Chp chemosensory system controls twitching motility and type IV pili biogenesis through control of pili assembly and/or retraction as well as expression of the pilin subunit gene pilA. The Chp system is also required for full virulence in a mouse model of acute pneumonia.