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Background: Textbook outcomes are composite outcome measures that reflect the ideal overall experience for patients. There are many of these in the elective surgery literature but no textbook outcomes have been proposed for patients following emergency laparotomy. The aim was to achieve international consensus amongst experts and patients for the best Textbook Outcomes for non-trauma and trauma emergency laparotomy. Methods: A modified Delphi exercise was undertaken with three planned rounds to achieve consensus regarding the best Textbook Outcomes based on the category, number and importance (Likert scale of 1–5) of individual outcome measures. There were separate questions for non-trauma and trauma. A patient engagement exercise was undertaken after round 2 to inform the final round. Results: A total of 337 participants from 53 countries participated in all three rounds of the exercise. The final Textbook Outcomes were divided into ‘early’ and ‘longer-term’. For non-trauma patients the proposed early Textbook Outcome was ‘Discharged from hospital without serious postoperative complications (Clavien–Dindo ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation or death). For trauma patients it was ‘Discharged from hospital without unexpected transfusion after haemostasis, and no serious postoperative complications (adapted Clavien–Dindo for trauma ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation on or death)’. The longer-term Textbook Outcome for both non-trauma and trauma was ‘Achieved the early Textbook Outcome, and restoration of baseline quality of life at 1 year’. Conclusion: Early and longer-term Textbook Outcomes have been agreed by an international consensus of experts for non-trauma and trauma emergency laparotomy. These now require clinical validation with patient data.

We propose an abstract conceptual framework for analysing complex security systems using a new notion of modes and mode transitions. A mode is an independent component of a system with its own objectives, monitoring data, algorithms, and scope and limits. The behaviour of a mode, including its transitions to other modes, is determined by interpretations of the mode's monitoring data in the light of its objectives and capabilities -- these interpretations we call beliefs. We formalise the conceptual framework mathematically and, by quantifying and visualising beliefs in higher-dimensional geometric spaces, we argue our models may help both design, analyse and explain systems. The mathematical models are based on simplicial complexes.

Existing indoor closed ultraviolet-C (UVC) air purifiers (UVC in a box) have faced technological challenges during the COVID-19 breakout, owing to demands of low energy consumption, high flow rates, and high kill rates at the same time. A new conceptual design of a novel UVC-LED (light-emitting diode) air purifier for a low-cost solution to mitigate airborne diseases is proposed. The concept focuses on performance and robustness. It contains a dust-filter assembly, an innovative UVC chamber, and a fan. The low-cost dust filter aims to suppress dust accumulation in the UVC chamber to ensure durability and is conceptually shown to be easily replaced while mitigating any possible contamination. The chamber includes novel turbulence-generating grids and a novel LED arrangement. The turbulent generator promotes air mixing, while the LEDs inactivate the pathogens at a high flow rate and sufficient kill rate. The conceptual design is portable and can fit into ventilation ducts. Computational fluid dynamics and UVC ray methods were used for analysis. The design produces a kill rate above 97% for COVID and tuberculosis and above 92% for influenza A at a flow rate of 100 L/s and power consumption of less than 300 W. An analysis of the dust-filter performance yields the irradiation and flow fields.

Congenital myopathies are a vast group of genetic muscle diseases. Among the causes are mutations in the MYH2 gene resulting in truncated type IIa myosin heavy chains (MyHCs). The precise cellular and molecular mechanisms by which these mutations induce skeletal muscle symptoms remain obscure. Hence, in the present study, we aimed to explore whether such genetic defects would alter the presence as well as the post-translational modifications of MyHCs and the functionality of myosin molecules. For this, we dissected muscle fibers from four myopathic patients with MYH2 truncating mutations and from five human healthy controls. We then assessed 1) MyHCs presence/post-translational modifications using LC/MS; 2) relaxed myosin conformation and concomitant ATP consumption with a loaded Mant-ATP chase setup; 3) myosin activation with an unloaded in vitro motility assay; and 4) cellular force production with a myofiber mechanical setup. Interestingly, the type IIa MyHC with one additional acetylated lysine (Lys35-Ac) was present in the patients. This was accompanied by 1) a higher ATP demand of myosin heads in the disordered-relaxed conformation; 2) faster actomyosin kinetics; and 3) reduced muscle fiber force. Overall, our findings indicate that MYH2 truncating mutations impact myosin presence/functionality in human adult mature myofibers by disrupting the ATPase activity and actomyosin complex. These are likely important molecular pathological disturbances leading to the myopathic phenotype in patients., Congenital myopathies are a vast group of genetic muscle diseases. Among the causes are mutations in the MYH2 gene resulting in truncated type IIa myosin heavy chains (MyHCs). The precise cellular and molecular mechanisms by which these mutations induce skeletal muscle symptoms remain obscure. Hence, in the present study, we aimed to explore whether such genetic defects would alter the presence as well as the post-translational modifications of MyHCs and the functionality of myosin molecules. For this, we dissected muscle fibers from four myopathic patients with MYH2 truncating mutations and from five human healthy controls. We then assessed 1) MyHCs presence/post-translational modifications using LC/MS; 2) relaxed myosin conformation and concomitant ATP consumption with a loaded Mant-ATP chase setup; 3) myosin activation with an unloaded in vitro motility assay; and 4) cellular force production with a myofiber mechanical setup. Interestingly, the type IIa MyHC with one additional acetylated lysine (Lys35-Ac) was present in the patients. This was accompanied by 1) a higher ATP demand of myosin heads in the disordered-relaxed conformation; 2) faster actomyosin kinetics; and 3) reduced muscle fiber force. Overall, our findings indicate that MYH2 truncating mutations impact myosin presence/functionality in human adult mature myofibers by disrupting the ATPase activity and actomyosin complex. These are likely important molecular pathological disturbances leading to the myopathic phenotype in patients.

BACKGROUND: Grasses populate most biogeographical zones, and their diversity influences allergic sensitisation to pollen. Previously, the contribution of different Poaceae subfamilies to airborne pollen has mostly been inferred from historical herbarium records. We recently applied environmental (e)DNA metabarcoding at one subtropical site revealing that successive airborne grass pollen peaks were derived from repeated flowering of Chloridoid and Panicoid grasses over a season. This study aimed to compare spatiotemporal patterns in grass pollen exposure across seasons and climate zones. METHODS: Airborne pollen concentrations across two austral pollen seasons spanning 2017-2019 at subtropical (Mutdapilly and Rocklea, Queensland) and temperate (Macquarie Park and Richmond, New South Wales) sites, were determined with a routine volumetric impaction sampler and counting by light microscopy. Poaceae rbcL metabarcode sequences amplified from daily pollen samples collected once per week were assigned to subfamily and genus using a ribosomal classifier and compared with Atlas of Living Australia sighting records. RESULTS: eDNA analysis revealed distinct dominance patterns of grass pollen at various sites: Panicoid grasses prevailed in both subtropical Mutdapilly and temperate Macquarie Park, whilst Chloridoid grasses dominated the subtropical Rocklea site. Overall, subtropical sites showed significantly higher proportion of pollen from Chloridoid grasses than temperate sites, whereas the temperate sites showed a significantly higher proportion of pollen from Pooideae grasses than subtropical sites. Timing of airborne Pooid (spring), Panicoid and Chloridoid (late spring to autumn), and Arundinoid (autumn) pollen were significantly related to number of days from mid-winter. Proportions of eDNA for subfamilies correlated with distributions grass sighting records between climate zones. CONCLUSIONS: eDNA analysis enabled finer taxonomic discernment of Poaceae pollen records acr

Most of the recent work in psychedelic neuroscience has been done using non-invasive neuroimaging, with data recorded from the brains of adult volunteers under the influence of a variety of drugs. While this data provides holistic insights into the effects of psychedelics on whole-brain dynamics, the effects of psychedelics on the meso-scale dynamics of cortical circuits remains much less explored. Here, we report the effects of the serotonergic psychedelic N,N-diproptyltryptamine (DPT) on information-processing dynamics in a sample of in vitro organotypic cultures made from rat cortical tissue. Three hours of spontaneous activity were recorded: an hour of pre-drug control, and hour of exposure to 10$\mu$M DPT solution, and a final hour of washout, once again under control conditions. We found that DPT reversibly alters information dynamics in multiple ways: first, the DPT condition was associated with higher entropy of spontaneous firing activity and reduced the amount of time information was stored in individual neurons. Second, DPT also reduced the reversibility of neural activity, increasing the entropy produced and suggesting a drive away from equilibrium. Third, DPT altered the structure of neuronal circuits, decreasing the overall information flow coming into each neuron, but increasing the number of weak connections, creating a dynamic that combines elements of integration and disintegration. Finally, DPT decreased the higher-order statistical synergy present in sets of three neurons. Collectively, these results paint a complex picture of how psychedelics regulate information processing in meso-scale cortical tissue. Implications for existing hypotheses of psychedelic action, such as the Entropic Brain Hypothesis, are discussed., Comment: 19 pages, 2 figures

Advanced AI models hold the promise of tremendous benefits for humanity, but society needs to proactively manage the accompanying risks. In this paper, we focus on what we term "frontier AI" models: highly capable foundation models that could possess dangerous capabilities sufficient to pose severe risks to public safety. Frontier AI models pose a distinct regulatory challenge: dangerous capabilities can arise unexpectedly; it is difficult to robustly prevent a deployed model from being misused; and, it is difficult to stop a model's capabilities from proliferating broadly. To address these challenges, at least three building blocks for the regulation of frontier models are needed: (1) standard-setting processes to identify appropriate requirements for frontier AI developers, (2) registration and reporting requirements to provide regulators with visibility into frontier AI development processes, and (3) mechanisms to ensure compliance with safety standards for the development and deployment of frontier AI models. Industry self-regulation is an important first step. However, wider societal discussions and government intervention will be needed to create standards and to ensure compliance with them. We consider several options to this end, including granting enforcement powers to supervisory authorities and licensure regimes for frontier AI models. Finally, we propose an initial set of safety standards. These include conducting pre-deployment risk assessments; external scrutiny of model behavior; using risk assessments to inform deployment decisions; and monitoring and responding to new information about model capabilities and uses post-deployment. We hope this discussion contributes to the broader conversation on how to balance public safety risks and innovation benefits from advances at the frontier of AI development., Comment: Update July 11th: - Added missing footnote back in. - Adjusted author order (mistakenly non-alphabetical among the first 6 authors) and adjusted affiliations (Jess Whittlestone's affiliation was mistagged and Gillian Hadfield had SRI added to her affiliations) Updated September 4th: Various typos

Item does not contain fulltext, BACKGROUND: Treatment with the aminoglycoside antibiotic gentamicin can be associated with severe adverse effects, including renal Ca(2+) wasting. The underlying mechanism is unknown but it has been proposed to involve activation of the Ca(2+)-sensing receptor (CaSR) in the thick ascending limb, which would increase expression of claudin-14 (CLDN14) and limit Ca(2+) reabsorption. However, no direct evidence for this hypothesis has been presented. METHODS: We studied the effect of gentamicin in vivo using mouse models with impaired Ca(2+) reabsorption in the proximal tubule and the thick ascending limb. We used a Cldn14 promoter luciferase reporter assay to study CaSR activation and investigated the effect of gentamicin on activity of the distal nephron Ca(2+) channel transient receptor potential vanilloid 5 (TRPV5), as determined by patch clamp in HEK293 cells. RESULTS: Gentamicin increased urinary Ca(2+) excretion in wild-type mice after acute and chronic administration. This calciuretic effect was unaltered in mice with genetic CaSR overactivation and was present in furosemide-treated animals, whereas the calciuretic effect in Cldn14(-/-) mice and mice with impaired proximal tubular Ca(2+) reabsorption (claudin-2 [CLDN2]-deficient Cldn2(-/-) mice) was equivalent to that of wild-type mice. In vitro, gentamicin failed to activate the CaSR. In contrast, patch clamp analysis revealed that gentamicin strongly inhibited rabbit and human TRPV5 activity and chronic gentamicin administration downregulated distal nephron Ca(2+) transporters. CONCLUSIONS: Gentamicin does not cause hypercalciuria via activation of the CaSR-CLDN14 pathway or by interfering with proximal tubular CLDN2-dependent Ca(2+) reabsorption. Instead, gentamicin blocks distal Ca(2+) reabsorption by direct inhibition of the Ca(2+) channel TRPV5. These findings offer new insights into Ca(2+) wasting in patients treated with gentamicin.

Aims The aims of this study were to determine antimicrobial prescription patterns and the factors affecting antimicrobial selection amongst Australian dairy veterinarians. Methods A structured questionnaire was administered to Australian dairy cattle veterinarians using the Qualtrics online survey platform. Questions focused on their (1) demographics; (2) opinions surrounding antimicrobial use, resistance, and stewardship; (3) decision-making drivers of both prescription and selection of commonly prescribed antimicrobials; (4) awareness on the guidelines for antimicrobial usage and sources of information concerning antimicrobials. Key results A total of 135 responses (14.1% response rate) from all eight dairying regions in Australia were received. The attitudes, perceptions, and concerns of dairy veterinarians towards antimicrobials indicated a high agreement regarding label indications (96%), consequences of off-label prescription (95%), and the presence of an antimicrobial resistance (AMR) risk (73%), when prescribing antibiotics. A four-dimensional categorical principal components analysis (CATPCA) model indicated most of the variation in opinion was due to AMR risk, trade-offs, prescription concerns and active substance concerns. The first active substance most dairy veterinarians chose for a scenario involving mastitis and dry cow therapy (DCT) treatment was cloxacillin. Decision-making drivers for antimicrobial choice when providing advice regarding the supply of antimicrobials for mastitis and DCT treatment were predominately clinical factors; however, diagnostics were rarely used in determining antimicrobial choice due to cost of implementation, diagnostic accuracy (sensitivity, specificity), and benefit issues. Non-clinical decision-making drivers included the perception of practicality for Australian Veterinary Association (AVA) prescription guidelines, opinions surrounding AMR risk and prescription concerns, consideration of Expert Advisory Group on Antim

Species composition is a key determinant of grassland ecosystem function and resilience. Climate change is predicted to alter the distribution of cool season (C3) and warm season (C4) grasses, however, the lack of spatial distributions and temporal variations of grass functional type information severely limits our understanding of climate impacts on grasslands. This study classified C3 and C4 grasses per pixel according to the peak of growing season generated from Enhanced Vegetation Index time series. From 2003 to 2017, the C3-C4 composition of Australian rain-fed grasslands and pastures was mapped at 500 m resolution on an annual basis across a wide geographical range (10°S – 45°S), and revealed extreme inter-annual fluctuations. Over the 15-year period, the satellite-derived ratio of C4 to C3 grasses significantly increased (p < 0.05), indicating a long-term shift in community composition that was confirmed with 182,911 Atlas of Living Australia ground observations. The most pronounced changes occurred in mid-latitude transitional areas where C3 and C4 grasses co-dominate. Our climate analysis indicated the inter-annual fluctuations of C4/C3 grass ratios were significantly associated (p < 0.05) with warm/cool season rainfall ratios, and not with temperature or annual rainfall. This suggests that an increase in the warm/cool season rainfall ratio favors C4 grasses and a decrease in the warm/cool season rainfall ratio favors C3 grasses. Our findings reveal spatially-detailed dynamics of grasslands and demonstrate large-scale grassland compositional changes over 15 years. The grass composition maps should help improve ecological forecasting of grass distributions and enable researches on grassland ecosystem responses to climate change that are relevant to both adaptation of rangeland agricultural and fire manag

Background: Allergic rhinitis affects half a billion people globally, including a fifth of the Australian population. As the foremost outdoor allergen source, ambient grass pollen exposure is likely to be altered by climate change. The AusPollen Partnership aimed to standardize pollen monitoring and examine broad-scale biogeographical and meteorological factors influencing interannual variation in seasonality of grass pollen aerobiology in Australia. Methods: Daily airborne grass and other pollen concentrations in four eastern Australian cities separated by over 1700 km, were simultaneously monitored using Hirst-style samplers following the Australian Interim Pollen and Spore Monitoring Standard and Protocols over four seasons from 2016 to 2020. The grass seasonal pollen integral was determined. Gridded rainfall, temperature, and satellite-derived grassland sources up to 100 km from the monitoring site were analysed. Results: The complexity of grass pollen seasons was related to latitude with multiple major summer-autumn peaks in Brisbane, major spring and minor summer peaks in Sydney and Canberra, and single major spring peaks occurring in Melbourne. The subtropical site of Brisbane showed a higher proportion of grass out of total pollen than more temperate sites. The magnitude of the grass seasonal pollen integral was correlated with pasture greenness, rainfall and number of days over 30 °C, preceding and within the season, up to 100 km radii from monitoring sites. Conclusions: Interannual fluctuations in Australian grass pollen season magnitude are strongly influenced by regional biogeography and both pre- and in-season weather. This first continental scale, Southern Hemisphere standardized aerobiology dataset forms the basis to track shifts in pollen seasonality, biodiversity and impacts on allergic respiratory diseases.

Recruiting, training and retaining scientists in computational biology is necessary to develop a workforce that can lead the quantitative biology revolution. Yet, African-American/Black, Hispanic/Latinx, Native Americans, and women are severely underrepresented in computational biosciences. We established the UCLA Bruins-in-Genomics Summer Research Program to provide training and research experiences in quantitative biology and bioinformatics to undergraduate students with an emphasis on students from backgrounds underrepresented in computational biology. Program assessment was based on number of applicants, alumni surveys and comparison of post-graduate educational choices for participants and a control group of students who were accepted but declined to participate. We hypothesized that participation in the Bruins-in-Genomics program would increase the likelihood that students would pursue post-graduate education in a related field. Our surveys revealed that 75% of Bruins-in-Genomics Summer participants were enrolled in graduate school. Logistic regression analysis revealed that women who participated in the program were significantly more likely to pursue a Ph.D. than a matched control group (group x woman interaction term of p = 0.005). The Bruins-in-Genomics Summer program represents an example of how a combined didactic-research program structure can make computational biology accessible to a wide range of undergraduates and increase participation in quantitative biosciences.

This study aimed to determine the similarity between and within positions in professional rugby league in terms of technical performance and match displacement. Here, the analyses were repeated on 3 different datasets which consisted of technical features only, displacement features only, and a combined dataset including both. Each dataset contained 7617 observations from the 2018 and 2019 Super League seasons, including 366 players from 11 teams. For each dataset, feature selection was initially used to rank features regarding their importance for predicting a player's position for each match. Subsets of 12, 11, and 27 features were retained for technical, displacement, and combined datasets for subsequent analyses. Hierarchical cluster analyses were then carried out on the positional means to find logical groupings. For the technical dataset, 3 clusters were found: (1) props, loose forwards, second-row, hooker; (2) halves; (3) wings, centres, fullback. For displacement, 4 clusters were found: (1) second-rows, halves; (2) wings, centres; (3) fullback; (4) props, loose forward, hooker. For the combined dataset, 3 clusters were found: (1) halves, fullback; (2) wings and centres; (3) props, loose forward, hooker, second-rows. These positional clusters can be used to standardise positional groups in research investigating either technical, displacement, or both constructs within rugby league.

PurposeTo explore trends in sexual orientation group differences in suicidality among Indigenous adolescents and evaluate whether gaps between heterosexual and sexual minority/Two-Spirit adolescents have changed over time.MethodsLeveraging pooled school-based population data from five waves of the British Columbia Adolescent Health Survey (1998-2018), we used age-adjusted logistic regression models, separately for boys and girls, to examine 20-year trends and disparities in past year suicidal ideation and suicide attempts among heterosexual and sexual minority/Two-Spirit Indigenous adolescents (N = 13,788).ResultsSuicidal ideation increased among all sexual orientation groups in 2018 compared to previous survey waves. Suicide attempts spiked for heterosexual girls in 2003, remained stable for heterosexual boys, and decreased for sexual minority/Two-Spirit boys and girls over time. Compared to their heterosexual peers, sexual minority/Two-Spirit boys had higher odds of suicidal ideation since 1998, whereas sexual minority/Two-Spirit girls had higher odds of suicidal ideation since 2003. Sexual minority/Two-Spirit (vs. heterosexual) boys were approximately 4-7 times more likely to attempt suicide since 2008, whereas sexual-minority/Two-Spirit (vs. heterosexual) girls were approximately 3-4 times more likely to attempt suicide since 2003. These gaps in suicidality were persistent across time.DiscussionSexual minority/Two-Spirit Indigenous adolescents are at an elevated risk for suicidality compared to their heterosexual Indigenous peers. While trends of suicidal ideation worsened for all Indigenous adolescents, suicide attempts either lessened or remained stable over time. Greater efforts are needed to help reduce suicidality among Indigenous adolescents in Canada, especially among sexual minority/Two-Spirit young people.

BACKGROUND: Allergic rhinitis affects half a billion people globally, including a fifth of the Australian population. As the foremost outdoor allergen source, ambient grass pollen exposure is likely to be altered by climate change. The AusPollen Partnership aimed to standardize pollen monitoring and examine broad-scale biogeographical and meteorological factors influencing interannual variation in seasonality of grass pollen aerobiology in Australia. METHODS: Daily airborne grass and other pollen concentrations in four eastern Australian cities separated by over 1700 km, were simultaneously monitored using Hirst-style samplers following the Australian Interim Pollen and Spore Monitoring Standard and Protocols over four seasons from 2016 to 2020. The grass seasonal pollen integral was determined. Gridded rainfall, temperature, and satellite-derived grassland sources up to 100 km from the monitoring site were analysed. RESULTS: The complexity of grass pollen seasons was related to latitude with multiple major summer-autumn peaks in Brisbane, major spring and minor summer peaks in Sydney and Canberra, and single major spring peaks occurring in Melbourne. The subtropical site of Brisbane showed a higher proportion of grass out of total pollen than more temperate sites. The magnitude of the grass seasonal pollen integral was correlated with pasture greenness, rainfall and number of days over 30 °C, preceding and within the season, up to 100 km radii from monitoring sites. CONCLUSIONS: Interannual fluctuations in Australian grass pollen season magnitude are strongly influenced by regional biogeography and both pre- and in-season weather. This first continental scale, Southern Hemisphere standardized aerobiology dataset forms the basis to track shifts in pollen seasonality, biodiversity and impacts on allergic respiratory diseases.

BackgroundImpairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (<50 years) is rising, there is little data on functional outcomes in this group.MethodsThe REACCT international collaborative database was reviewed and data on eligible patients analysed. Inclusion criteria comprised patients with a histologically confirmed rectal cancer, <50 years of age at time of diagnosis and with documented follow-up including functional outcomes.ResultsA total of 1428 (n=1428) patients met the eligibility criteria and were included in the final analysis. Metastatic disease was present at diagnosis in 13%. Of these, 40% received neoadjuvant therapy and 50% adjuvant chemotherapy. The incidence of post-operative major morbidity was 10%. A defunctioning stoma was placed for 621 patients (43%); 534 of these proceeded to elective restoration of bowel continuity. The median follow-up time was 42 months. Of this cohort, a total of 415 (29%) reported persistent impairment of functional outcomes, the most frequent of which was bowel dysfunction (16%), followed by bladder dysfunction (7%), sexual dysfunction (4.5%) and infertility (1%).ConclusionA substantial proportion of patients with early-onset rectal cancer who undergo surgery report persistent impairment of functional status. Patients should be involved in the discussion regarding their treatment options and potential impact on quality of life. Functional outcomes should be routinely recorded as part of follow up alongside oncological parameters.

When providing pollen forecasts to the community, there is a need to verify the accuracy of curated forecasts, but evaluation is not routinely reported. This study of the AusPollen Partnership compared multi-category grass pollen forecasts for up to six days ahead with daily airborne grass pollen concentrations measured in Brisbane, Canberra, Melbourne, and Sydney, Australia during four pollen seasons from 2016 to 2020. The accuracy of categorical grass pollen forecasts predicting grass pollen concentrations in the high and greater, or moderate and greater categories, were assessed as often applied in meteorology using Gerrity scores, equitable threat scores, false alarm ratios, success ratios, and probability of detection of correct category. The skill of grass pollen forecasts curated by aerobiologists were compared with two retrospectively calculated naïve reference forecast methods; climatology and persistence. For Brisbane and Melbourne, high or greater grass pollen levels occurred on average 32% and 22% of days, whereas for Canberra and Sydney, there were few high days, but moderate or greater pollen levels occurred on average 26% and 19% of days, respectively. Average annual Gerrity scores for curated forecasts of high or greater improved with experience from 0.20 to 0.66 in Brisbane, and from 0.39 to 0.55 in Melbourne between 2016 and 2019. Average Gerrity Scores for moderate or greater categories in Sydney were 0.45 and 0.43 in 2016 and 2018 respectively, and in Canberra were 0.34 and 0.41, in the same years. The skill of curated forecasts was usually better than persistence forecasts, but the accuracy of the curated forecasts decreased with longer lead times. Although persistence grass pollen forecasts consistently performed better than climatologies, persistence depends on previous day pollen concentrations being available. Short-term curated daily grass pollen forecasts of the AusPollen Partnership offer useful information for people with allergic rhinit

The International Bottom Trawl Survey Working Group (IBTSWG) coordinates fishery-independent bottom trawl surveys in the ICES area in the Northeast Atlantic and the North Sea. These long-term monitoring surveys provide data for stock assessments and facilitate examina-tion of changes in fish distribution and relative abundance. The group also promotes the stand-ardization of fishing gears and methods as well as survey coordination. This report summarizes the national contributions in 2021–2022 and plans for the 2022–2023 surveys coordinated by IBTSWG.

TREs are widely, and increasingly used to support statistical analysis of sensitive data across a range of sectors (e.g., health, police, tax and education) as they enable secure and transparent research whilst protecting data confidentiality. There is an increasing desire from academia and industry to train AI models in TREs. The field of AI is developing quickly with applications including spotting human errors, streamlining processes, task automation and decision support. These complex AI models require more information to describe and reproduce, increasing the possibility that sensitive personal data can be inferred from such descriptions. TREs do not have mature processes and controls against these risks. This is a complex topic, and it is unreasonable to expect all TREs to be aware of all risks or that TRE researchers have addressed these risks in AI-specific training. GRAIMATTER has developed a draft set of usable recommendations for TREs to guard against the additional risks when disclosing trained AI models from TREs. The development of these recommendations has been funded by the GRAIMATTER UKRI DARE UK sprint research project. This version of our recommendations was published at the end of the project in September 2022. During the course of the project, we have identified many areas for future investigations to expand and test these recommendations in practice. Therefore, we expect that this document will evolve over time.

The rise of AI in human contexts places new demands on automated systems to be transparent and explainable. We examine some anthropomorphic ideas and principles relevant to such accountablity in order to develop a theoretical framework for thinking about digital systems in complex human contexts and the problem of explaining their behaviour. Structurally, systems are made of modular and hierachical components, which we abstract in a new system model using notions of modes and mode transitions. A mode is an independent component of the system with its own objectives, monitoring data, and algorithms. The behaviour of a mode, including its transitions to other modes, is determined by functions that interpret each mode's monitoring data in the light of its objectives and algorithms. We show how these belief functions can help explain system behaviour by visualising their evaluation as trajectories in higher-dimensional geometric spaces. These ideas are formalised mathematically by abstract and concrete simplicial complexes. We offer three techniques: a framework for design heuristics, a general system theory based on modes, and a geometric visualisation, and apply them in three types of human-centred systems., Comment: Comments welcome

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity.

The MJA-Lancet Countdown on health and climate change in Australia was established in 2017 and produced its first national assessment in 2018 and annual updates in 2019, 2020 and 2021. It examines five broad domains: climate change impacts, exposures and vulnerability; adaptation, planning and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement. In this, the fifth year of the MJA-Lancet Countdown, we track progress on an extensive suite of indicators across these five domains, accessing and presenting the latest data and further refining and developing our analyses. Within just two years, Australia has experienced two unprecedented national catastrophes - the 2019-2020 summer heatwaves and bushfires and the 2021-2022 torrential rains and flooding. Such events are costing lives and displacing tens of thousands of people. Further, our analysis shows that there are clear signs that Australia's health emergency management capacity substantially decreased in 2021. We find some signs of progress with respect to health and climate change. The states continue to lead the way in health and climate change adaptation planning, with the Victorian plan being published in early 2022. At the national level, we note progress in health and climate change research funding by the National Health and Medical Research Council. We now also see an acceleration in the uptake of electric vehicles and continued uptake of and employment in renewable energy. However, we also find Australia's transition to renewables and zero carbon remains unacceptably slow, and the Australian Government's continuing failure to produce a national climate change and health adaptation plan places the health and lives of Australians at unnecessary risk today, which does not bode well for the future.

The International Bottom Trawl Survey Working Group (IBTSWG) coordinates fishery-independent bottom trawl surveys in the ICES area in the Northeast Atlantic and the North Sea. These long-term monitoring surveys provide data for stock assessments and facilitate examination of changes in fish distribution and relative abundance. The group also promotes the standardization of fishing gears and methods as well as survey coordination. This report summarizes the national contributions in 2021–2022 and plans for the 2022–2023 surveys coordinated by IBTSWG. In the North Sea, the surveys are performed in quarters (Q) Q1 and Q3, while in the Northeast Atlantic the surveys are conducted in Q1, Q3, and Q4 with a suite of 14 national surveys covering a large area of continental shelf that extends from the north of Scotland to the Gulf of Cádiz. North Sea surveys in 2022-Q1 were affected severely by mechanical and COVID-related issues, as well as the number of storms experienced during the survey period. Some of the ICES rectangles in the survey area could not be sampled and a larger number of the rectangles were only sampled with a single tow. North Sea surveys in 2021-Q3 were broadly complete, with the wider area surveyed and comparable number of hauls. However, some rectangles close to shore or with obstructions may not have had full coverage. Most of the surveys in the Northeast Atlantic were completed successfully. However, the two Spanish groundfish surveys in the Gulf of Cádiz could not be undertaken in 2021. Vessel-related problems also affected the Spanish survey of the Cantabrian Sea, although this survey was completed using two vessels over a more protracted survey window. The IBTSWG welcomed the return of the Portuguese groundfish survey (Q4) after a two-year absence, with the survey being undertaken by the new research vessel, the “Mario Ruivo”. IBTSWG discussed the roadmap for the new survey trawl, following on from the Workshop o

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity.

Species composition is a key determinant of grassland ecosystem function and resilience. Climate change is predicted to alter the distribution of cool season (C3) and warm season (C4) grasses, however, the lack of spatial distributions and temporal variations of grass functional type information severely limits our understanding of climate impacts on grasslands. This study classified C3 and C4 grasses per pixel according to the peak of growing season generated from Enhanced Vegetation Index time series. From 2003 to 2017, the C3-C4 composition of Australian rain-fed grasslands and pastures was mapped at 500 m resolution on an annual basis across a wide geographical range (10°S – 45°S), and revealed extreme inter-annual fluctuations. Over the 15-year period, the satellite-derived ratio of C4 to C3 grasses significantly increased (p < 0.05), indicating a long-term shift in community composition that was confirmed with 182,911 Atlas of Living Australia ground observations. The most pronounced changes occurred in mid-latitude transitional areas where C3 and C4 grasses co-dominate. Our climate analysis indicated the inter-annual fluctuations of C4/C3 grass ratios were significantly associated (p < 0.05) with warm/cool season rainfall ratios, and not with temperature or annual rainfall. This suggests that an increase in the warm/cool season rainfall ratio favors C4 grasses and a decrease in the warm/cool season rainfall ratio favors C3 grasses. Our findings reveal spatially-detailed dynamics of grasslands and demonstrate large-scale grassland compositional changes over 15 years. The grass composition maps should help improve ecological forecasting of grass distributions and enable researches on grassland ecosystem responses to climate change that are relevant to both adaptation of rangeland agricultural and fire management practices. Our study should also help predict grass distribution under future climate conditions, and assist in the accurate modelling of global water

ImportanceThe incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.ObservationsWithin the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and relevanceThe clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Background Empyema is a serious complication of pneumonia frequently caused by Streptococcus pneumoniae (SP). We assessed the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema after inclusion in the Australian National Immunisation Program. Methods For bacterial pneumonia and empyema hospitalisations, we ascertained incidence rates (IRs) using the National Hospital Morbidity Database International Statistical Classification of Disease discharge codes and relevant population denominators, and calculated incidence rate ratios (IRR) comparing the 13vPCV period (June 2012-May 2017) with the 7vPCV period (June 2007-May 2011). Blood and pleural fluid (PF) cultures and PF PCR of 401 children with empyema from 11 Australian hospitals during the 13vPCV period were compared with our previous study in the 7vPCV period. Findings Across 7vPCV and 13vPCV periods, IRs per million children (95% CIs) were 1605 (1588 to 1621) and 1272 (1259 to 1285) for bacterial pneumonia, and 14.23 (12.67 to 15.79) and 17.89 (16.37 to 19.42) for empyema hospitalisations. IRRs were 0.79 (0.78 to 0.80) for bacterial pneumonia and 1.25 (1.09 to 1.44) for empyema. Of 161 empyema cases with SP serotypes, 147 (91.3%) were vaccine types. ST3 accounted for 76.4% of identified serotypes in the 13vPCV period, more than double than the 7vPCV period (p<0.001); ST19A decreased from 36.4% to 12.4%. No cases of ST1 empyema were identified in the 13vPCV period versus 14.5% in the 7vPCV period. Interpretation 13vPCV resulted in a significant reduction in all-cause hospitalisations for bacterial pneumonia but empyema hospitalisations significantly increased, with emergence of pneumococcal ST3 as the dominant serotype in empyema. Trial registration number Australian and New Zealand Clinical Trial Registry ACTRN 12614000354684.

Contains fulltext : 234024.pdf (Publisher’s version ) (Closed access), PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Background Empyema is a serious complication of pneumonia frequently caused by Streptococcus pneumoniae (SP). We assessed the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema after inclusion in the Australian National Immunisation Program. Methods For bacterial pneumonia and empyema hospitalisations, we ascertained incidence rates (IRs) using the National Hospital Morbidity Database International Statistical Classification of Disease discharge codes and relevant population denominators, and calculated incidence rate ratios (IRR) comparing the 13vPCV period (June 2012-May 2017) with the 7vPCV period (June 2007-May 2011). Blood and pleural fluid (PF) cultures and PF PCR of 401 children with empyema from 11 Australian hospitals during the 13vPCV period were compared with our previous study in the 7vPCV period. Findings Across 7vPCV and 13vPCV periods, IRs per million children (95% CIs) were 1605 (1588 to 1621) and 1272 (1259 to 1285) for bacterial pneumonia, and 14.23 (12.67 to 15.79) and 17.89 (16.37 to 19.42) for empyema hospitalisations. IRRs were 0.79 (0.78 to 0.80) for bacterial pneumonia and 1.25 (1.09 to 1.44) for empyema. Of 161 empyema cases with SP serotypes, 147 (91.3%) were vaccine types. ST3 accounted for 76.4% of identified serotypes in the 13vPCV period, more than double than the 7vPCV period (p<0.001); ST19A decreased from 36.4% to 12.4%. No cases of ST1 empyema were identified in the 13vPCV period versus 14.5% in the 7vPCV period. Interpretation 13vPCV resulted in a significant reduction in all-cause hospitalisations for bacterial pneumonia but empyema hospitalisations significantly increased, with emergence of pneumococcal ST3 as the dominant serotype in empyema. Trial registration number Australian and New Zealand Clinical Trial Registry ACTRN 12614000354684. Copyright © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy. In some patients, HIT causes platelet activation and thrombosis (sometimes abbreviated HITT), which leads to adverse clinical sequalae ('pathological HIT'). The likelihood of HIT is initially assessed clinically, typically using a scoring system, of which the 4T score is that most utilised. Subsequent laboratory testing to confirm or exclude HIT facilitates exclusion or diagnosis and management. The current investigation comprises a multicentre (n=9) assessment of contemporary laboratory testing for HIT, as performed over the past 1-3 years in each site and comprising testing of over 1200 samples. The primary laboratory test used by study participants (n=8) comprised a chemiluminescence procedure (HIT-IgG(PF4-H)) performed on an AcuStar instrument. Additional immunological testing performed by study sites included lateral flow (STiC, Stago), enzyme linked immunosorbent assay (ELISA), Asserachrom (HPIA IgG), PaGIA (BioRad), plus functional assays, primarily serotonin release assay (SRA) or platelet aggregation methods. The chemiluminescence procedure yielded a highly sensitive screening method for identifying functional HIT, given high area under the curve (AUC, generally >=0.9) in a receiver operator characteristic (ROC) analysis against SRA as gold standard. ELISA testing resulted in lower ROC AUC scores (<0.8) and higher levels of false positives. Although there is clear association with the likelihood of HIT, the 4T score had less utility than literature suggests, and was comparable to a previous study reported by some of the authors.Copyright © 2020

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal disorder caused by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency. Prompt identification/exclusion of TTP can thus be facilitated by rapid ADAMTS13 testing. The most commonly utilized (enzyme-linked immunosorbent assay [ELISA]-based) assay takes several hours to perform and so does not generally permit rapid testing. Objective(s): To evaluate the utility of a new automated test for ADAMTS13 activity, the HemosIL AcuStar ADAMTS13 Activity assay, based on chemiluminescence and able to be performed on an ACL AcuStar instrument within 33 minutes. Patients/Methods: This multicenter (n = 8) assessment included testing of more than 700 test samples, with similar numbers of prospective (n = 348) and retrospective (n = 385) samples. The main comparator was the Technozym ADAMTS13 Activity ELISA. We also assessed comparative performance for detection of ADAMTS13 inhibitors using a Bethesda assay. Result(s): Overall, the chemiluminescent assay yielded similar results to the comparator ELISA, albeit with slight negative bias. ADAMTS13 inhibitor detection was also comparable, albeit with slight positive bias with the AcuStar assay. Assay precision was similar with both assays, and we also verified assay normal reference ranges. Conclusion(s): The HemosIL AcuStar ADAMTS13 Activity assay provided results rapidly, which were largely comparable with the Technozym ADAMTS13 Activity ELISA assay, albeit lower on average. Conversely, inhibitor levels tended to be identified at a higher level on average. Thus, the HemosIL AcuStar ADAMTS13 Activity assay provides a fast and accurate means to quantitate plasma levels of ADAMTS13 for TTP/ADAMTS13 identification/exclusion, and potentially also for other applications.Copyright © 2020 International Society on Thrombosis and Haemostasis

IMPORTANCE The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. OBSERVATIONS Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include aWesternized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. CONCLUSIONS AND RELEVANCE The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1 beta subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.