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Abstract Background Juvenile polyposis syndrome (JPS), a rare autosomal dominant syndrome, affects one per 100 000 births, increasing lifetime cancer risk by 9 – 50%. Around 40–60% of JPS cases are caused by disease-causing variants (DCV) in SMAD4 or BMPR1A genes, of which SMAD4 accounts for 20–30%. Objectives To characterise genotype–phenotype correlations between sites and types of variants within SMAD4 to JPS phenotypes, to inform diagnosis, screening, and management of JPS. Search methods Online search databases utilised included Ovid MEDLINE, Embase Classic + Embase and PubMed, using search terms classified by MeSH on Demand. Adjacency operators, word truncation and Boolean operators were employed. 110 articles were included in the review, collating 291 variants from the literature. Results In SMAD4 + JPS patients, most variants are located around SMAD4’s MH2 domain (3’ end). Extracolonic involvement, massive gastric polyposis and a more aggressive phenotype have been associated with SMAD4 + JPS, predisposing to gastric cancer. This has contributed to an overall higher incidence of GI cancers compared to other genes causing JPS, with DCVs mostly all within the MH2 domain. Genetically related allelic disorders of SMAD4 also have variants in this region, including hereditary haemorrhagic telangiectasia (HHT) alongside SMAD4 + JPS, and Myhre syndrome, independent of JPS. Similarly, with DCVs in the MH2 domain, Ménétrier’s disease, hypertrophic osteoarthropathy and juvenile idiopathic arthritis have been seen in this population, whereas cardiac pathologies have occurred both alongside and independently of SMAD4 + JPS with DCVs in the MH1 domain. Conclusion Truncating and missense variants around the MH2 region of SMAD4 are most prevalent and pathogenic, thus should undergo careful surveillance. Given association with extracolonic polyposis and higher GI cancer risk, endoscopic screening should occur more frequently and at an earlier age in SMAD4 + JPS patients than in patients with other causative genes, with consideration of Ménétrier’s disease on upper GI endoscopy. In addition, HHT should be evaluated within 6 months of diagnosis, alongside targeted clinical examination for extraintestinal manifestations associated with SMAD4 + JPS. This review may help modify clinical diagnosis and management of SMAD4 + JPS patients, and aid pathogenicity classification for SMAD4 DCVs through a better understanding of the phenotypes.

Abstract The gold-standard treatment for Parkinson’s disease is levodopa (L-DOPA), which is taken orally and absorbed intestinally. L-DOPA must reach the brain intact to exert its clinical effect; peripheral metabolism by host and microbial enzymes is a clinical management issue. The gut microbiota is altered in PD, with one consistent and unexplained observation being an increase in Bifidobacterium abundance among patients. Recently, certain Bifidobacterium species were shown to have the ability to metabolize L-tyrosine, an L-DOPA structural analog. Using both clinical cohort data and in vitro experimentation, we investigated the potential for commensal Bifidobacteria to metabolize this drug. In PD patients, Bifidobacterium abundance was positively correlated with L-DOPA dose and negatively with serum tyrosine concentration. In vitro experiments revealed that certain species, including B. bifidum, B. breve, and B. longum, were able to metabolize this drug via deamination followed by reduction to the compound 3,4-dihydroxyphenyl lactic acid (DHPLA) using existing tyrosine-metabolising genes. DHPLA appears to be a waste product generated during regeneration of NAD +. This metabolism occurs at low levels in rich medium, but is significantly upregulated in nutrient-limited minimal medium. Discovery of this novel metabolism of L-DOPA to DHPLA by a common commensal may help inform medication management in PD.

Abstract Background Australia persistently has one of the highest rates of colorectal cancer (CRC) in the world. Australia’s National Bowel Cancer Screening Program (NBCSP) sends a biennial Faecal Immunochemical Test (FIT)—the ‘NBCSP kit’—to everyone eligible for the programme between 50 and 74 years old; however, participation in the programme is low, especially in the 50- to 60-year-old age group. Our previous efficacy trial (‘SMARTscreen’) demonstrated an absolute increase in uptake of 16.5% (95% confidence interval = 2.02–30.9%) for people sent an SMS with motivational and instructional videos, from their general practice prior to receiving their NBCSP kit, compared to those receiving usual care. Building on the strengths of the SMARTscreen trial and addressing limitations, the ‘SMARTERscreen’ trial will test the effect on participation in the NBCSP of sending either an SMS only or an SMS with online video material to general practice patients due to receive their NBCSP compared to ‘usual care’. Methods SMARTERscreen is a three-arm stratified cluster randomised controlled trial involving 63 general practices in two states in Australia. Eligible patients are patients who are aged 49–60 years and due to receive their NBCSP kit within the next 2 weeks during the intervention period. General practices will be equally randomised to three trial arms (21:21:21, estimated average 260 patients/practice). The two interventions include (i) an SMS with an encouraging message from their general practice or (ii) the same SMS with weblinks to additional motivational and instructional videos. The control arm will receive ‘usual care’. Using the intention-to-treat approach, primary analysis will estimate the three pair-wise between-arm differences in the proportion of eligible patients who participate in the NBCSP within 6 months of when their kit is sent, utilising screening data from the Australian National Cancer Screening Register (NCSR). Patient intervention adherence to the interventions will also be evaluated. Findings will be incorporated into the Policy1-Bowel microsimulation model to estimate the long-term health benefits and cost-effectiveness of the interventions. Discussion SMARTERscreen will provide high-level evidence determining whether an SMS or an SMS with web-based material sent to general practice patients prior to receiving their NBCSP kit increases participation in bowel cancer screening. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12623000036617. Registered on 13 January 2023. Trial URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385119&isClinicalTrial=False

Background: Mechanisms sustaining persistent atrial fibrillation (AF) remain unclear. Objectives: The study sought to evaluate both the clinical outcomes and response to ablation of potential drivers in patients with recurrent persistent AF recurrence following pulmonary vein isolation (PVI). Methods: A total of 100 patients with persistent AF of 1.5 revolutions or focal activations. Cycle lengths were measured pre- and postablation. The primary outcome was freedom from atrial arrhythmia off antiarrhythmic drugs at 1 year as per guidelines. Results: Of 37 patients recruited, 26 had recurrent AF and underwent ECGI-guided ablation of PDs. An average of 6.4 ± 2.7 PDs were targeted per patient. The mean ablation time targeting PDs was 15.5 ± 6.9 minutes. An ablation response occurred in 20 patients (AF termination in 6, cycle length prolongation ≥10% in 14). At 1 year, 14 (54%) of 26 patients were free from arrhythmia, and 12 (46%) of 26 were off antiarrhythmic drugs. Considering the 96 patients who completed follow-up out of the original cohort of 100 patients undergoing cryoablation in this staged strategy, freedom from arrhythmia at 1 year following the last procedure was 72 (75%) of 96, or 70 (73%) of 96 off antiarrhythmic drugs. Conclusions: In patients with recurrent AF despite PVI, ECGI-guided ablation caused an acute response in a majority with reasonable long-term outcomes.

Abstract Laser-plasma accelerators are compact linear accelerators based on the interaction of high-power lasers with plasma to form accelerating structures up to 1000 times smaller than standard radiofrequency cavities, and they come with an embedded X-ray source, namely betatron source, with unique properties: small source size and femtosecond pulse duration. A still unexplored possibility to exploit the betatron source comes from combining it with imaging methods able to encode multiple information like transmission and phase into a single-shot acquisition approach. In this work, we combine edge illumination-beam tracking (EI-BT) with a betatron X-ray source and present the demonstration of multimodal imaging (transmission, refraction, and scattering) with a compact light source down to the femtosecond timescale. The advantage of EI-BT is that it allows multimodal X-ray imaging technique, granting access to transmission, refraction and scattering signals from standard low-coherence laboratory X-ray sources in a single shot.

Background and Objectives: We previously reported on the impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the QoL of persons with ME/CFS and their family members. Here, we present the findings of the impact on the QoL of individuals with ME/CFS whose family members did not participate in the survey. Materials and Methods: A prospective multinational online survey was disseminated via patient charities, support groups and social media. Persons with ME/CFS completed the EuroQoL questionnaire (EQ-5D-3L). Results: Data were analysed from 876 participants from 26 countries who reported a health care professional diagnosis of ME/CFS. In total, 742 participants identified as female, 124 male and 10 preferred not to say. The mean age of the participants was 47 years (range 18–82), and the mean time to diagnosis was 14 years. The mean overall health status on a visual analogue scale for people with ME/CFS was 36.4 (100 = best health). People with ME/CFS were most often affected by inability to perform usual activities (n = 852, 97%), followed by pain (n = 809, 92%), impaired mobility (n = 724, 83%), difficulty in self-care (n = 561, 64%) and least often affected by anxiety and depression (n = 540, 62%). Conclusions: The QoL of people with ME/CFS is significantly affected globally. There was no significant difference in quality of life compared with previously published data on those with ME/CFS who did have a family member complete the family member quality of life questionnaire (FROM16). Contrary to popular misconception, anxiety and depression are the least often affected areas in persons with ME/CFS who are most impacted by their inability to perform usual activities.

Mass timber construction has recently gained popularity due to its outstanding environmental benefits and building performance, which hold revolutionary potential for the construction industry. However, its impacts from the perspective of occupants have not been thoroughly explored. This study introduces an innovative empirical approach that explores the potential benefits of mass timber construction for individuals and organizations, with an emphasis on the workplace. We review the conceptual framework regarding how visual and physical exposure to timber construction materials and finishes have a positive effect on individuals and organizations at a broad level. We propose a more holistic mixed-method behavioral approach to studying occupant behavior and well-being by integrating self-reported questionnaires, objective biomarkers (heart rate variability and hair cortisol), and indoor environmental quality (IEQ) measures. Our study offers a novel research primer on the exploration of mass timber construction impacts and benefits for both office workers and construction workers. Participants from different office settings completed pre- and post-occupancy evaluation surveys to assess their experiences, including IEQ satisfaction, productivity, and health. Office workers were located in three different offices: a controlled laboratory environment, an open-plan office, and an open-plan space with a timber interior. The construction workers worked in a timber space for three months and then moved to work in a building with a concrete structure. The analysis included descriptive statistics, t-tests, ANOVA, and linear regression to compare differences between office settings and assess the relationship between environmental variables and overall satisfaction in IEQ, comfort, productivity, and health. In office workers, in terms of building image, thermal comfort, and artificial lighting, the data analysis revealed significant differences in occupants’ satisfaction levels between office settings. However, the low number of participants affected the results, and some factors were not found significant in relation to the office setting. Among tradespeople, there was no relationship between the building environment and productivity, health, or comfort. However, the results of hair cortisol testing indicated that working in a timber space can decrease the level of cortisol (stress) and have an impact on the productivity of workers. Such occupant’s perspective research is pivotal to informing policy makers, developers, business owners, construction professionals, timber industry stakeholders, environmentalists, and researchers in their decision-making processes. Fostering the future widespread adoption and advancement of mass timber construction.

BackgroundNon-germinomatous germ cell tumors (NGGCT) accounts for one third of intracranial GCT. While the germinoma group have an excellent overall survival, the standard of practice for children with NGGCT is still under evaluation.AimsDescribe the results of the of the Brazilian consortium protocol.MethodsSince 2013, 15 patients with a diagnosis of NGGCT by histopathology and/or serum/cerebrospinal fluid (CSF) tumor markers, βHCG >200mlU/ml and/or positive alpha-fetoprotein were treated with neoadjuvant chemotherapy with carboplatin, cyclophosphamide and etoposide followed by ventricular radiotherapy (RTV) of 18Gy with boost (32Gy) to the primary site. Metastatic patients underwent craniospinal irradiation (CSI) and “slow responders” to the four initial cycles of CT, to autologous stem cell transplantation (ASCT) followed by CSI.ResultsMean age, 13.1 years. Thirteen males. Primary sites: pineal (n=12), suprasellar (n=2) and bifocal (n=1). Four patients were metastatic at diagnosis. Eight patients had CSF and/or serum alpha-fetoprotein levels > 1,000ng/ml. Tumor responses after chemotherapy demonstrated complete in six cases and partial in seven, with “second-look” surgery being performed in five cases, and two patients presenting viable lesions being referred to ASCT. The main toxicity observed was hematological grades 3/4. Two patients with metastatic disease, one with Down Syndrome and AFP > 1,000ng/ml and the other with choriocarcinoma and pulmonary metastases, developed progressive disease resulting in death, as well as two other patients without evidence of disease, due to endocrinological disorders. Event-free and overall survival at 2 and 5 years were 80% and 72.7%, respectively, with a mean follow-up of 48 months (range, 7-107).ConclusionsDespite the small number of patients, in our series, treatment with six cycles of chemotherapy and RTV with focal boost for localized disease (n=11) and ACST for identified slow responders (n=2) seem to be effective strategies contributing to the overall effort to improve outcomes of this group of patients.

Abstract Conservation detection dogs (CDD) use their exceptional olfactory abilities to assist a wide range of conservation projects through the detection of target specimens or species. CDD are generally quicker, can cover wider areas and find more samples than humans and other analytical tools. However, their efficacy varies between studies; methodological and procedural standardisation in the field is lacking. Considering the cost of deploying a CDD team and the limited financial resources within conservation, it is vital that their performance is quantified and reliable. This review aims to summarise what is currently known about the use of scent detection dogs in conservation and elucidate which factors affect efficacy. We describe the efficacy of CDD across species and situational contexts like training and fieldwork. Reported sensitivities (i.e. the proportion of target samples found out of total available) ranged from 23.8% to 100% and precision rates (i.e. proportion of alerts that are true positives) from 27% to 100%. CDD are consistently shown to be better than other techniques, but performance varies substantially across the literature. There is no consistent difference in efficacy between training, testing and fieldwork, hence we need to understand the factors affecting this. We highlight the key variables that can alter CDD performance. External effects include target odour, training methods, sample management, search methodology, environment and the CDD handler. Internal effects include dog breed, personality, diet, age and health. Unfortunately, much of the research fails to provide adequate information on the dogs, handlers, training, experience and samples. This results in an inability to determine precisely why an individual study has high or low efficacy. It is clear that CDDs can be effective and applied to possibly limitless conservation scenarios, but moving forward researchers must provide more consistent and detailed methodologies so that comparisons can be conducted, results are more easily replicated and progress can be made in standardising CDD work.

Metastasis remains the leading cause of cancer deaths worldwide and lung cancer, known for its highly metastatic progression, remains among the most lethal of malignancies. Lung cancer metastasis can selectively spread to multiple different organs, however the genetic and molecular drivers for this process are still poorly understood. Understanding the heterogeneous genomic profile of lung cancer metastases is considered key in identifying therapeutic targets that prevent its spread. Research has identified the key source for metastasis being clusters of cells rather than individual cancer cells. These clusters, known as metastatic cancer cell clusters (MCCCs) have been shown to be 100-fold more tumorigenic than individual cancer cells. Unfortunately, access to these primary drivers of metastases remains difficult and has limited our understanding of their molecular and genomic profiles. Strong evidence in the literature suggests that differentially regulated biological pathways in MCCCs can provide new therapeutic drug targets to help combat cancer metastases. In order to expand research into MCCCs and their role in metastasis, we demonstrate a novel, proof of principle technology, to capture MCCCs directly from patients' whole blood. Our platform can be readily tuned for different solid tumor types by combining a biomimicry-based margination effect coupled with immunoaffinity to isolate MCCCs. Adopting a selective capture approach based on overexpressed CD44 in MCCCs provides a methodology that preferentially isolates them from whole blood. Furthermore, we demonstrate a high capture efficiency of more than 90% when spiking MCCC-like model cell clusters into whole blood. Characterization of the captured MCCCs from lung cancer patients by immunofluorescence staining and genomic analyses, suggests highly differential morphologies and genomic profiles. This study lays the foundation to identify potential drug targets thus unlocking a new area of anti-metastatic therapeutics.

Hybrid whole genome sequencing was used to investigate if nosocomial Verona integron-encoded metallo-β-lactamase (VIM) carbapenemase transmission occurred between two patients without epidemiological links or common pathogens. Challenges in genomic methodology and appropriate analytical depth for mobile carbapenemase outbreaks are described including how inappropriate choices can mislead results and impact infection control practices.

There is an increasing need for valid, rapid diet screening tools. A significant association between the Prime Diet Quality Score (PDQS) and reduced risk of cardiovascular disease (CVD) has been demonstrated in the US but evidence of its use in Europe is lacking. The aim of this study was to amend the PDQS for a UK/Irish population and determine validity and reliability in those at risk of CVD. Participants were recruited via online adverts across the island of Ireland. The PDQS was amended for a UK/Irish population and participants completed PDQS and reference measure (4-day food diary (FD)) on two occasions. PDQS score was calculated directly from PDQS and indirectly from FDs. Validity was determined using Spearman correlation coefficients (SCCs) (r), intraclass correlation coefficients (ICCs) and weighted kappa. Reliability was determined using SCCs (r), ICCs, weighted kappa and coefficient of variation.

Purpose: The Australian Genomics Cardiovascular Disorders Flagship was a national multidisciplinary collaboration. It aimed to investigate the feasibility of genome sequencing (GS) and functional genomics to resolve variants of uncertain significance (VUS) in the clinical management of patients and families with cardiomyopathies, primary arrhythmias, and congenital heart disease (CHD). Methods: Between April 2019 and December 2021, 600 probands meeting cardiovascular disorder criteria from 17 cardiology and genetics clinics across Australia were enrolled in the Flagship and underwent GS. The Flagship adopted a tiered approach to GS analysis. Tier 1 analysis assessed genes with established clinical validity for each cardiovascular condition. Tier 2 analysis assessed lesser-evidenced research-based genes. Tier 3 analysis assessed the functional impact of VUS that remained after tier 1 and tier 2 analysis. Results: Overall, a pathogenic or likely pathogenic variant was identified in 41% of participants with a cardiomyopathy, 40% with an arrhythmia syndrome, and 15% with a familial CHD/CHD+Extra Cardiac Anomalies. A VUS outcome ranged from 13% for arrhythmias to 34% for CHD/CHD+Extra Cardiac Anomalies participants. Tier 2 research analysis identified a likely pathogenic/pathogenic variant for a further 15 participants and a VUS for an additional 15 participants. Conclusion: The Flagship successfully facilitated a model of care that harnesses clinical GS and functional genomics for the resolution of VUS in the clinical setting. This valuable data set can be used to inform clinical practice and facilitate research into the future.

Thousands of offshore oil and gas platforms have been installed throughout the world's oceans and more structures are being installed as part of the transition to renewable energy. These structures increase the availability of ecological niches by providing hard substrate in midwater and complex 3D habitat on the seafloor. This can lead to 'hotspots' of biodiversity, or increased densities of flora and fauna, which potentially spill over into the local area. However, the distances over which these higher densities extend (the 'range of influence') can be highly variable. Fish aggregate at such structures, but the range of influence and any implications for wider fish populations, are unclear. We investigated the relationship between fish and platform areal densities using high resolution fisheries acoustic data. Data were collected in the waters surrounding the vessel exclusions zones around 16 oil and gas platforms in the North Sea, and throughout the wider area. We estimated densities of schooling fish using echo-integration, and densities of non-schooling fish using echo-counting. At 10 platforms, non-schooling fish densities were elevated near the platform relative to background levels in the equivalent wider area. The range of influence, defined here as the range to which fish densities were elevated above background, varied from 0.8 to 23 km. In areas of high platform density, fish schools were encountered more often, and non-schooling fish densities were higher, when controlling for other sources of environmental variation. This is the first time such long-range effects have been identified; previously, ranges of influence have been reported in the order of just 10s-100s of metres. These findings suggest that the environmental impact of these structures may extend further than previously thought, which may be relevant in the context of upcoming management decisions around the decommissioning of these structures.

Sourdough technology has been known for its role in the improvement of texture, flavor, and quality of mainly wheat and rye-based breads for decades. However, little is reported about its use in the improvement of whole-grain oat bread, especially concerning flavor formation, which is one major consumer drivers. This study investigated the effects of sourdough obtained by different lactic acid bacteria and yeast starters consortia on the texture and flavor of 100% oat bread. Four different consortia were selected to obtain four oat sourdoughs, which were analyzed to assess the main features due to the different starter fermentation metabolism. Sourdoughs were added to breads as 30% dough weight. Bread quality was technologically monitored via hardness and volume measurements. Sourdough breads were softer and had higher specific volume. The sensory profile of sourdoughs and breads was assessed by a trained panel in sensory laboratory conditions, and the volatile profile was analyzed by HS-SPME-GC-MS. Sourdoughs were rated with higher intensities than untreated control for most of attributes, especially concerning sour aroma and flavor attributes. Sourdough breads were rated with higher intensities than control bread for sour vinegar flavor and total odor intensity, in addition they had richer volatile profile. Our results confirmed that sourdough addition can lead to an enhanced flavor, moreover, it demonstrated that the use of different consortia of lactic acid bacteria and yeast strains leads to the improvement of texture and altered sensory profile of whole-oat bread.

Little is known about longer-term changes to community participation since the COVID-19 pandemic onset and potential implications for health and wellbeing in later life. This multi-method investigation analyzes national data from the COVID-19 Coping Study. Statistical analyses of survey data (n = 1,630; mean age 67.9 years; data collected April/May 2022) identified that adults residing in the US still tended to stay inside their homes more often since the pandemic onset. Overall, participants decreased their engagement with amenities such as eateries, gyms, and arts and cultural sites. Reflexive thematic analysis of semi-structured in-depth interviews (n = 57; mean age 70.7 years; data collected May-July 2021) identified altered community participation with perceived long-term impacts on physical, mental, and social health and wellbeing. The results provide novel insights about the critical nature of ‘third places’ to support later life, and policy implications to strengthen community environments. Investment in outdoor, well-ventilated, and distanced third places may support wellbeing.

Fish in coastal ecosystems can be exposed to acute variations in CO2 of between 0.2 and 1 kPa CO2 (2000-10,000 µatm). Coping with this environmental challenge will depend on the ability to rapidly compensate for the internal acid-base disturbance caused by sudden exposure to high environmental CO2 (blood and tissue acidosis); however, studies about the speed of acid-base regulatory responses in marine fish are scarce. We observed that upon sudden exposure to ∼1 kPa CO2, European sea bass (Dicentrarchus labrax) completely regulate erythrocyte intracellular pH within ∼40 min, thus restoring haemoglobin-O2 affinity to pre-exposure levels. Moreover, blood pH returned to normal levels within ∼2 h, which is one of the fastest acid-base recoveries documented in any fish. This was achieved via a large upregulation of net acid excretion and accumulation of HCO3- in blood, which increased from ∼4 to ∼22 mmol l-1. While the abundance and intracellular localisation of gill Na+/K+-ATPase (NKA) and Na+/H+ exchanger 3 (NHE3) remained unchanged, the apical surface area of acid-excreting gill ionocytes doubled. This constitutes a novel mechanism for rapidly increasing acid excretion during sudden blood acidosis. Rapid acid-base regulation was completely prevented when the same high CO2 exposure occurred in seawater with experimentally reduced HCO3- and pH, probably because reduced environmental pH inhibited gill H+ excretion via NHE3. The rapid and robust acid-base regulatory responses identified will enable European sea bass to maintain physiological performance during large and sudden CO2 fluctuations that naturally occur in coastal environments.