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Abstract Background Clinical prediction models (CPMs) estimate an individual’s risk of current or future outcome events, using information available about the individual at the time of prediction. While most CPMs are developed to predict a single outcome event, many clinical decisions require considering the risks of multiple outcome events. For example, decision-making for anticoagulation therapy involves assessing an individual’s risks of both blood clot and bleeding, while decision-making around interventions for multimorbidity prevention requires an understanding of the risks of developing multiple long-term conditions. However, determining when and how to incorporate multiple outcomes into CPMs remains challenging. This article aims to raise awareness of multiple outcome prediction and present clinical examples where such prediction is essential to help inform individual decision-making. Main text A range of analytical methods are available to develop multiple-outcome CPMs, but there are frequent malapropisms and heterogeneity in terminology across this literature, making it difficult to identify/compare possible methods. Selecting the appropriate method should depend on the intended risk estimand—the type of predicted risks that we wish the CPM to estimate—but this is often not defined or reported. Using clinical examples and a decision-analytical perspective, we present a taxonomy of risk estimands to frame different clinical contexts requiring multiple-outcome CPMs. We outline four levels of risk estimands: (i) single-outcome risk, (ii) competing-outcome risk, (iii) composite-outcome risk, and (iv) risk of multiple outcome combinations. We demonstrate how a decision-analytical and utility-theory lens can help define the risk estimand for a given clinical scenario, based on the model’s intended use. Conclusions Clearly defining and reporting the risk estimand is essential for all prediction model studies. A decision-analytical framework aids in selecting the most appropriate estimand for a given prediction task and in determining when and how to incorporate multiple outcomes into CPM development.

Abstract. This article provides an overview of the current evidence on the epidemiology, overlapping risk factors, and pathophysiology of cardiovascular disease (CVD) in patients with cancer. It explores the cardiotoxic effects of anticancer therapy and their impact on prognosis. Although cancer survival rates have improved over the last two decades, the risk of CVD has risen over time in patients with cancer. CVD and cancer share similar risk factors and a common pathophysiology involving inflammation. Many chemotherapeutic agents used to treat cancer are associated with cardiovascular complications (such as heart failure, myocardial infarction, and thrombosis). Current evidence indicates a significant burden of CVD in patients with cancer, particularly in the first year following cancer diagnosis, with elevated risk persisting beyond this period. This short- and long-term risk of CVD may vary depending on the cancer type and treatment regimen. Early identification of potential cardiovascular risk in patients with cancer, can lead to more favorable clinical and survival outcomes. Given the acute and long-term consequences, patients with cancer require increased cardiovascular care and lifestyle optimization. This article offers valuable insights into the cardiovascular burden and needs of patients with cancer. It is intended for a general medical research readership interested in the intersection of cardiology and oncology.

Abstract Aims Clinical pathways have been shown to improve outcomes in patients with heart failure (HF). Although patients with HF often have a cardiac implantable electronic device, few studies have reported the utility of device‐derived risk scores to augment and organize care. TriageHF Plus is a device‐based HF clinical pathway (DHFP) that uses remote monitoring alerts to trigger structured telephone assessment for HF stability and optimization. We aimed to evaluate the impact of TriageHF Plus on hospitalizations and describe the associated workforce burden. Methods and results TriageHF Plus was a multi‐site, prospective study that compared outcomes for patients recruited between April 2019 and February 2021. All alert‐triggered assessments were analysed to determine the appropriateness of the alert and the workload burden. A negative‐binomial regression with inverse probability treatment weighting using a time‐matched usual care cohort was applied to estimate the effect of TriageHF Plus on non‐elective hospitalizations. A post hoc pre‐COVID‐19 sensitivity analysis was also performed. The TriageHF Plus cohort (n = 443) had a mean age of 68.8 ± 11.2 years, 77% male (usual care cohort: n = 315, mean age of 66.2 ± 14.5 years, 65% male). In the TriageHF Plus cohort, an acute medical issue was identified following an alert in 79/182 (43%) cases. Fifty assessments indicated acute HF, requiring clinical action in 44 cases. At 30 day follow‐up, 39/66 (59%) of initially symptomatic patients reported improvement, and 20 (19%) initially asymptomatic patients had developed new symptoms. On average, each assessment took 10 min. The TriageHF Plus group had a 58% lower rate of hospitalizations across full follow‐up [incidence relative ratio: 0.42, 95% confidence interval (CI): 0.23–0.76, P = 0.004]. Across the pre‐COVID‐19 window, hospitalizations were 31% lower (0.69, 95% CI: 0.46–1.04, P = 0.077). Conclusions These data represent the largest real‐world evaluation of a DHFP based on multi‐parametric risk stratification. The TriageHF Plus clinical pathway was associated with an improvement in HF symptoms and reduced all‐cause hospitalizations.

IntroductionDuring the summer of 2021, western Canada experienced a historic and deadly extreme heat event. Simultaneously, toxic drug use and overdoses related to high-risk use of opioids and polysubstance use continued to rise across the country. However, the combined impacts of these intersecting public health crises remain poorly understood as relevant data sources are limited in Canada.MethodsWe explored news media articles (n = 86, 3%) discussing toxic drug use, overdose-related deaths and the 2021 Heat Dome which were identified in a systematic review of Canadian online news media (e.g., newspaper articles, radio broadcasts) from five subscription news databases and an extensive grey literature search (n = 2909). The analyzed articles were published before, during and after the 2021 Heat Dome, and were qualitatively coded and thematically analyzed in NVivo to identify patterns of meaning across the dataset.ResultsFour main themes were identified within our media-based analysis: (I) the reported impact of toxic drug use on human thermoregulation and behavioural adaptation; (II) the reported demand of intersecting crises on the health system; (III) barriers and stigma reported to influence an individual's access to or use of heat mitigation behaviours and services; and (IV) the reported impact of extreme heat on the public health response to drug poisoning emergencies.ConclusionWith increasing temperature extremes and a rising tide of toxic drug use and overdoses, our findings illustrate that there is a need for further research to better understand the combined impacts when toxic drug use, overdose-related deaths, and extreme heat coincide.

Objectives: Heat-health communication initiatives are a key public health protection strategy. Therefore, understanding the potential challenges that all Canadians and specific groups, such as those facing literacy barriers and non-native language speakers, may experience in accessing or interpreting information, is critical. Methods: This study reviewed and evaluated the language availability, readability, suitability, and comprehensibility of heat-related webpages and online resources (n = 417) published on public health authority websites in Canada (n = 73). Six validated readability scales and a comprehensibility instrument were used. Results: Most content was presented in English (90 %); however, only 7 % of the online resources were available in more than one language. The average reading grade level of the content (grade 8) exceeded the recommended level (grade 6), and only 22 % of the content was deemed superior for suitability and comprehensibility. Conclusions: Our study evaluating web-based materials about extreme heat published by Canadian health authorities provides evidence that the current language availability, readability, suitability, and comprehensibility may be limiting the capacity for members of the public to discern key messaging. Innovation: To ensure all Canadians can access and interpret information related to heat-health protection, public health authorities may consider translating their materials into additional languages and incorporating a readability evaluation to improve public understanding.

Background: With the growing threat posed by extreme heat, heat-health messaging communicated by public health authorities is critical for raising community awareness and action. This study sought to (i) identify what heat-health content is shared online by Canadian public health authorities and (ii) analyse the material to develop an understanding of the content included within the resources. Study design: Qualitative content analysis. Methods: We reviewed public health authority websites in Canada (n = 99) and extracted all available heat-health content. Content analysis of each resource was performed using descriptive codes related to three categories - populations at greater risk, actions to reduce risk and awareness and knowledge. Results: Within the public health authority websites searched, 417 webpages and online resources were identified (range: 1–43). Over half of the material came from regional health authorities (56 %), primarily located in Ontario and British Columbia (60 %). At least one population at greater risk of heat stress (e.g., older adults, children) (range: 0–24) was mentioned in 59 % of the materials, 81 % mentioned at least one action or behaviour to reduce risk (e.g., stay hydrated) (range: 0–40), and 91 % provided material related to raising awareness and knowledge (range: 0–12). Conclusions: Although a wide array of webpages and online resources were identified, the material content and availability varied considerably across authorities and provinces and territories. These results provide important insights into the composition of heat-health webpages and online resources within Canada and can help guide relevant revisions and additions to the existing heat-health materials.

Summary: Background: Elevated body mass index (BMI) ≥25 kg/m2 is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m2, and cancer incidence, and compare this with single BMI. Methods: In this cohort study and individual participant data meta-analysis, we obtained data from the ABACus 2 Consortium, consisting of four US cohorts: Atherosclerosis Risk in Communities (ARIC) study (1987–2015), Women's Health Initiative (WHI; 1991 to 2005 [main study], to 2010 [Extension 1], and to 2020 [Extension 2]), Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial (1993–2009), NIH-AARP Diet and Health Study (1996–2011), and one European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC; participants enrolled in 1990 and administrative censoring was centre-specific). Participants with at least 3 BMI measurements and complete cancer follow-up data were included. We calculated overweight-years: degree of overweight (BMI ≥25 kg/m2) multiplied by the duration of overweight (years). Using random effects two-stage individual participant data meta-analyses, associations between cancer and overweight-years, single BMI, cumulative overweight degree and duration, measured at the same time and captured over a median of 41 years in men and 39 years in women, were evaluated with Cox proportional hazards models. Models were age-adjusted or multivariable (MV) adjusted for baseline age, ethnicity, alcohol, smoking and hormone replacement therapy (HRT). Harrell's C-statistic of metrics were compared. This study is registered at PROSPERO, CRD42021238270. Findings: 720,210 participants, including 312,132 men and 408,078 women, were followed up for cancer incidence over a median 9.85 years (interquartile range (IQR) 8.03, 11.67) in men and 10.80 years (IQR 6.05, 15.55) in women. 12,959 men (4.15%) and 36,509 women (8.95%) were diagnosed with obesity-related cancer. Hazard ratios for obesity-related cancers in men, per 1 standard deviation (SD) overweight-years were 1.15 (95% CI: 1.14, 1.16, I2: 0) age-adjusted and 1.15 (95% CI: 1.13, 1.17, I2: 0%) MV-adjusted and per 1SD increment in single BMI were 1.17 (95% CI: 1.16, 1.18, I2: 0) age-adjusted and 1.16 (95% CI: 1.15, 1.18, I2: 0%) MV-adjusted. The HR for overweight-years in women per 1 SD increment was 1.08 (95% CI: 1.04, 1.13, I2: 82%) age-adjusted and 1.08 (95% CI: 1.04, 1.13, I2: 83%) MV-adjusted and per 1SD increment in single BMI was 1.10 (95% CI: 1.07, 1.14, I2: 72%) age-adjusted and 1.11 (95% CI: 1.07, 1.15, I2: 79%) MV-adjusted. C-statistics for overweight-years and single BMI for obesity-related cancers were 0.612 (95% CI: 0.578, 0.646) and 0.611 (95% CI: 0.578, 0.644) respectively for men and 0.566 (95% CI: 0.534, 0.598) and 0.573 (95% CI: 0.546, 0.600) for women. Interpretation: Adulthood degree and duration of excess BMI were associated with cancer risk. Both factors should be considered in cancer prevention strategies and policies. This study only focused on adulthood exposure to excess BMI, so the minimal differences in the predictive performance between adiposity metrics may be due to underestimation of cumulative excess BMI exposure. Funding: Cancer Research UK, the Manchester NIHR Biomedical Research Centre, the National Cancer Institute, the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, U.S. Department of Health and Human Services, the Intramural Research Program of the National Cancer Institute, the International Agency for Research on Cancer, Imperial College London, European Commission (DG-SANCO), the Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, the Hellenic Health Foundation, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Health Research Fund, Instituto de Salud Carlos III, regional Spanish governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, the Catalan Institute of Oncology, Swedish Cancer Society, Swedish Scientific Council, and Region Skåne and Region Västerbotten, and the Medical Research Council.

Introduction: The understanding of the role of climate change in worsening health outcomes and social disparities is growing, highlighting poverty as a key factor amplifying exposure to environmental hazards and as a result of such exposure. However, there has been insufficient focus on the unique risks encountered in Canada, highlighting the necessity for targeted understanding to inform and evaluate effective responses. The question guiding the present scoping review is: In the Canadian context, what are the impacts and implications of climate change and weather extremes on the physical and mental health of those experiencing poverty, as evidenced in the peer-reviewed academic literature? Methods: A systematic search was conducted within the following four databases: Scopus, PubMed, PsycINFO, and Google Scholar, using key terms related to poverty, climate change, and health and well-being in the Canadian context. Primary research and review articles published in English were included (n = 28). Results: The articles included 23 reports of primary research and five reviews, spanning 2000 to 2022. Six theme areas emerged at the climate change, poverty, and health intersection in Canada: heat, air pollution, food security, pollen, wildfire evacuation, and health systems. Discussion: Addressing poverty reduction is identified as a critical lever for reducing environmental risks and enhancing resilience, although challenges remain in implementing evidence-based interventions due to significant gaps in knowledge. Future research should consider exploring outcomes disaggregated by sociodemographic factors, interconnections between heat and air pollution, and interventions targeting vulnerable groups.

DFT calculations demonstrate that an isoacenofuran of any size possesses a smaller HOMO–LUMO gap than the corresponding acene bearing an isoelectronic π-system (i.e., the same total number of rings). Isoacenofurans show limited stability due in part to the highly reactive 1,3-carbons of the furan ring. Both 1,3-dimesitylisobenzofuran and 1,3-di(2’,4’,6’-triethylphenyl)isobenzofuran, each bearing sterically congesting ortho-alkyl groups on their phenyl substituents, have been synthesized and shown to adopt non-planar conformations with the ortho-alkyl groups located above and below the most reactive 1,3-carbons of the furan ring. These bulky substituents provide a strong measure of kinetic stabilization. Thus, 1,3-dimesitylisobenzofuran and 1,3-di(2’,4’,6’-triethylphenyl)isobenzofuran are significantly less reactive than 1,3-diphenylisobenzofuran toward the strong dienophiles DMAD and acrylonitrile. The insights gained here suggest that the synthesis of large, persistent, kinetically stabilized isoacenofurans with unusually small HOMO–LUMO gaps is achievable. As such, these molecules deserve increased attention as potential p-type organic semiconductors.

The clearance of peripheral beta amyloid (Aβ) is a potential target for the treatment of Alzheimer’s disease (AD). The liver has been implicated in the elimination of Aβ from the peripheral circulation. Here, the single-pass uptake of Aβ40 in perfused livers from young and old rats (6 to 10 rats per group) was investigated with the multiple indicator dilution technique. Aβ40 had volumes of distribution between those of the vascular marker Evans Blue and the extracellular marker sucrose. The hepatic extraction of Aβ40 was negligible, explained in part by the small permeability surface area products consistent with a high endothelial barrier to liver uptake. There were no substantial effects of age on any of these results. In vitro experiments with isolated hepatocytes and liver sinusoidal endothelial cells showed only very small amounts of Aβ uptake consistent with low intrinsic clearance. These results indicate that the hepatic clearance of Aβ is capacity-limited, explained by the low-permeability surface area products and hepatocyte uptake. However, this does not preclude an effect of aging in longer-term in vivo studies where age-related changes in liver blood flow and protein binding influence liver clearance.

The unprecedented 2021 Heat Dome caused wide-ranging and long-lasting impacts in western Canada, including 619 confirmed heat-related deaths in British Columbia, a doubling of emergency medical calls, increased hospitalisations, infrastructure failures and stress on plants and animals. However, such varied socio-economic consequences of extreme heat can be challenging to capture using a single post-event analysis method. Therefore, there is a need to explore alternative approaches and data sources. Using the 2021 Heat Dome as a case study, a post-event analysis using online news media articles (n = 2909) from 5 subscription news databases and a grey literature search was conducted to identify the socio-economic impacts of the extreme heat event in Canada. The articles reported a wide range of effects to the natural environment (n = 1366), social infrastructure and services (n = 1121), human health (n = 1074), critical infrastructure (n = 988) and the private sector (n = 165). The media-based post-event analysis captured various impacts, some of which have not been identified through other data sources and approaches. Overall, we show that media analysis can complement traditional post-event analysis methods and provide additional perspectives to governments and public health and safety officials.

Abstract The brain derived‐neurotrophic factor (BDNF) Val66Met polymorphism causes functional changes in BDNF, and is associated with obesity and some psychiatric disorders, but its relationship to health‐related quality of life (HRQoL) remains unknown. This study examined, in youth with obesity, whether carriers of the BDNF Val66met polymorphism Met‐alleles (A/A or G/A) differed from noncarriers (G/G) on HRQoL. The participants were 187 adolescents with obesity. Ninety‐nine youth were carriers of the homozygous Val/Val (G/G) alleles, and 88 were carriers of the Val/Met (G/A) or Met/Met (A/A) alleles. Blood samples were drawn in the morning after an overnight fast for genotyping. HRQoL was measured using the Pediatric‐Quality of Life core version. Compared to carriers of the Val66Met Val (G/G) alleles, carriers of the Met‐Alleles reported significantly higher physical –HRQoL (p = 0.02), school‐related HRQoL, (p = 0.05), social‐related HRQoL (p = 0.05), and total HRQoL (p = 0.03), and a trend for Psychosocial‐HRQoL. Research is needed to confirm our findings and determine whether carriers of the BDNF Val66Met homozygous Val (G/G) alleles may be at risk of diminished HRQoL, information that can influence interventions in a high‐risk population of inactive youth with obesity.

Abstract Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.

Abstract The past decade has seen an increase in the prevalence of sequence type (ST) 45 methicillin-resistant Staphylococcus aureus (MRSA), yet the underlying drivers for its emergence and spread remain unclear. To better understand the worldwide dissemination of ST45 S. aureus, we performed phylogenetic analyses of Australian isolates, supplemented with a global population of ST45 S. aureus genomes. Our analyses revealed a distinct lineage of multidrug-resistant ST45 MRSA harbouring qacA, predominantly found in Australia and Singapore. Bayesian inference predicted that the acquisition of qacA occurred in the late 1990s. qacA was integrated into a structurally variable region of the chromosome containing Tn552 (carrying blaZ) and Tn4001 (carrying aac(6’)-aph(2”)) transposable elements. Using mutagenesis and in vitro assays, we provide phenotypic evidence that qacA confers tolerance to chlorhexidine. These findings collectively suggest both antimicrobial resistance and the carriage of qacA may play a role in the successful establishment of ST45 MRSA.

Abstract Background and aims Sepsis is a serious and life-threatening condition caused by a dysregulated immune response to an infection. Recent guidance issued in the UK gave recommendations around recognition and antibiotic treatment of sepsis, but did not consider factors relating to health inequalities. The aim of this study was to summarise the literature investigating associations between health inequalities and sepsis. Methods Searches were conducted in Embase for peer-reviewed articles published since 2010 that included sepsis in combination with one of the following five areas: socioeconomic status, race/ethnicity, community factors, medical needs and pregnancy/maternity. Results Five searches identified 1,402 studies, with 50 unique studies included in the review after screening (13 sociodemographic, 14 race/ethnicity, 3 community, 3 care/medical needs and 20 pregnancy/maternity; 3 papers examined multiple health inequalities). Most of the studies were conducted in the USA (31/50), with only four studies using UK data (all pregnancy related). Socioeconomic factors associated with increased sepsis incidence included lower socioeconomic status, unemployment and lower education level, although findings were not consistent across studies. For ethnicity, mixed results were reported. Living in a medically underserved area or being resident in a nursing home increased risk of sepsis. Mortality rates after sepsis were found to be higher in people living in rural areas or in those discharged to skilled nursing facilities while associations with ethnicity were mixed. Complications during delivery, caesarean-section delivery, increased deprivation and black and other ethnic minority race were associated with post-partum sepsis. Conclusion There are clear correlations between sepsis morbidity and mortality and the presence of factors associated with health inequalities. To inform local guidance and drive public health measures, there is a need for studies conducted across more diverse setting and countries.

Abstract Background Each year, thousands of clinical prediction models are developed to make predictions (e.g. estimated risk) to inform individual diagnosis and prognosis in healthcare. However, most are not reliable for use in clinical practice. Main body We discuss how the creation of a prediction model (e.g. using regression or machine learning methods) is dependent on the sample and size of data used to develop it—were a different sample of the same size used from the same overarching population, the developed model could be very different even when the same model development methods are used. In other words, for each model created, there exists a multiverse of other potential models for that sample size and, crucially, an individual’s predicted value (e.g. estimated risk) may vary greatly across this multiverse. The more an individual’s prediction varies across the multiverse, the greater the instability. We show how small development datasets lead to more different models in the multiverse, often with vastly unstable individual predictions, and explain how this can be exposed by using bootstrapping and presenting instability plots. We recommend healthcare researchers seek to use large model development datasets to reduce instability concerns. This is especially important to ensure reliability across subgroups and improve model fairness in practice. Conclusions Instability is concerning as an individual’s predicted value is used to guide their counselling, resource prioritisation, and clinical decision making. If different samples lead to different models with very different predictions for the same individual, then this should cast doubt into using a particular model for that individual. Therefore, visualising, quantifying and reporting the instability in individual-level predictions is essential when proposing a new model.

Background & Aims: Liver sinusoidal endothelial cells (LSECs) are important in liver development, regeneration, and pathophysiology, but the differentiation process underlying their tissue-specific phenotype is poorly understood and difficult to study because primary human cells are scarce. The aim of this study was to use human induced pluripotent stem cell (hiPSC)-derived LSEC-like cells to investigate the differentiation process of LSECs. Methods: hiPSC-derived endothelial cells (iECs) were transplanted into the livers of Fah−/−/Rag2−/−/Il2rg−/− mice and assessed over a 12-week period. Lineage tracing, immunofluorescence, flow cytometry, plasma human factor VIII measurement, and bulk and single cell transcriptomic analysis were used to assess the molecular and functional changes that occurred following transplantation. Results: Progressive and long-term repopulation of the liver vasculature occurred as iECs expanded along the sinusoids between hepatocytes and increasingly produced human factor VIII, indicating differentiation into LSEC-like cells. To chart the developmental profile associated with LSEC specification, the bulk transcriptomes of transplanted cells between 1 and 12 weeks after transplantation were compared against primary human adult LSECs. This demonstrated a chronological increase in LSEC markers, LSEC differentiation pathways, and zonation. Bulk transcriptome analysis suggested that the transcription factors NOTCH1, GATA4, and FOS have a central role in LSEC specification, interacting with a network of 27 transcription factors. Novel markers associated with this process included EMCN and CLEC14A. Additionally, single cell transcriptomic analysis demonstrated that transplanted iECs at 4 weeks contained zonal subpopulations with a region-specific phenotype. Conclusions: Collectively, this study confirms that hiPSCs can adopt LSEC-like features and provides insight into LSEC specification. This humanised xenograft system can be applied to further interrogate LSEC developmental biology and pathophysiology, bypassing current logistical obstacles associated with primary human LSECs. Impact and implications: Liver sinusoidal endothelial cells (LSECs) are important cells for liver biology, but better model systems are required to study them. We present a pluripotent stem cell xenografting model that produces human LSEC-like cells. A detailed and longitudinal transcriptomic analysis of the development of LSEC-like cells is included, which will guide future studies to interrogate LSEC biology and produce LSEC-like cells that could be used for regenerative medicine.

Healthcare organizations increasingly engage in activities to identify and address social determinants of health (SDOH) among their patients to improve health outcomes and reduce costs. While several studies to date have focused on the evolving role of hospitals and physicians in these types of population health activities, much less is known about the role health insurers may play. We used data from the National Longitudinal Survey of Public Health Systems for the period 2006 to 2018 to examine trends in health insurer participation in population health activities and in the multi-sector collaborative networks that support these activities. We also used a difference-in-differences approach to examine the impact of Medicaid expansion on insurer participation in population health networks. Insurer participation increased in our study period both in the delivery of population health activities and in the integration into collaborative networks that support these activities. Insurers were most likely to participate in activities focusing on community health assessment and policy development. Results from our adjusted difference-in-differences models showed variation in association between insurer participation in population health networks and Medicaid expansion (Table 2). Population health networks in expansion states experienced significant increases insurer participation in assessment (4.48 percentage points, P

OBJECTIVES (BACKGROUND):. To externally validate clinical prediction models that aim to predict progression to invasive ventilation or death on the ICU in patients admitted with confirmed COVID-19 pneumonitis. DESIGN:. Single-center retrospective external validation study. DATA SOURCES:. Routinely collected healthcare data in the ICU electronic patient record. Curated data recorded for each ICU admission for the purposes of the U.K. Intensive Care National Audit and Research Centre (ICNARC). SETTING:. The ICU at Manchester Royal Infirmary, Manchester, United Kingdom. PATIENTS:. Three hundred forty-nine patients admitted to ICU with confirmed COVID-19 Pneumonitis, older than 18 years, from March 1, 2020, to February 28, 2022. Three hundred two met the inclusion criteria for at least one model. Fifty-five of the 349 patients were admitted before the widespread adoption of dexamethasone for the treatment of severe COVID-19 (pre-dexamethasone patients). OUTCOMES:. Ability to be externally validated, discriminate, and calibrate. METHODS:. Articles meeting the inclusion criteria were identified, and those that gave sufficient details on predictors used and methods to generate predictions were tested in our cohort of patients, which matched the original publications’ inclusion/exclusion criteria and endpoint. RESULTS:. Thirteen clinical prediction articles were identified. There was insufficient information available to validate models in five of the articles; a further three contained predictors that were not routinely measured in our ICU cohort and were not validated; three had performance that was substantially lower than previously published (range C-statistic = 0.483–0.605 in pre-dexamethasone patients and C = 0.494–0.564 among all patients). One model retained its discriminative ability in our cohort compared with previously published results (C = 0.672 and 0.686), and one retained performance among pre-dexamethasone patients but was poor in all patients (C = 0.793 and 0.596). One model could be calibrated but with poor performance. CONCLUSIONS:. Our findings, albeit from a single center, suggest that the published performance of COVID-19 prediction models may not be replicated when translated to other institutions. In light of this, we would encourage bedside intensivists to reflect on the role of clinical prediction models in their own clinical decision-making.

BackgroundMost existing clinical prediction models do not allow predictions under interventions. Such predictions allow predicted risk under different proposed strategies to be compared and are therefore useful to support clinical decision making. We aimed to compare methodological approaches for predicting individual level cardiovascular risk under three interventions: smoking cessation, reducing blood pressure, and reducing cholesterol.MethodsWe used data from the PREDICT prospective cohort study in New Zealand to calculate cardiovascular risk in a primary care setting. We compared three strategies to estimate absolute risk under intervention: (a) conditioning on hypothetical interventions in non-causal models; (b) combining existing prediction models with causal effects estimated using observational causal inference methods; and (c) combining existing prediction models with causal effects reported in published literature.ResultsThe median absolute cardiovascular risk among smokers was 3.9%; our approaches predicted that smoking cessation reduced this to a median between a non-causal estimate of 2.5% and a causal estimate of 2.8%, depending on estimation methods. For reducing blood pressure, the proposed approaches estimated a reduction of absolute risk from a median of 4.9% to a median between 3.2% and 4.5% (both derived from causal estimation). Reducing cholesterol was estimated to reduce median absolute risk from 3.1% to between 2.2% (non-causal estimate) and 2.8% (causal estimate).ConclusionsEstimated absolute risk reductions based on non-causal methods were different to those based on causal methods, and there was substantial variation in estimates within the causal methods. Researchers wishing to estimate risk under intervention should be explicit about their causal modelling assumptions and conduct sensitivity analysis by considering a range of possible approaches.

Abstract The Intergovernmental Panel on Climate Change (IPCC) has been a crucial facilitator of climate change research and governance. After its sixth assessment cycle, the organization is at a critical juncture. The amount of climate science has grown tremendously over the past three decades, but so has global emissions of greenhouse gases. If the world is to reach the objectives implied by the Paris Agreement, climate action must accelerate on an unprecedented scale and pace, across widely differing contexts. Scientific knowledge will play a key role in this endeavour. Everyone who produces or relies on climate knowledge needs to wrestle with this pivotal question: How can IPCC processes and outcomes be reformed to produce knowledge that is more relevant for climate action? The organizational and resource constraints of the IPCC must be considered when searching for answers. This is an introduction to a special collection of research articles, reviews and perspectives dealing with this question from many different angles. In this introduction, we present four possible reform agendas for the IPCC in the form of ideal types, all with their advantages and disadvantages. This introduction does not advocate a certain set of reforms but rather attempts to spur discussions and reflections on the IPCC and its future.

Abstract Mitigation scenarios have become an important element of Intergovernmental Panel on Climate Change (IPCC) reports. We critically assess the curation of the IPCC mitigation scenarios database, with a focus on improving curation and utilisation. The existing method of curation favours particular models, and results may have limited statistical meaning. We draw lessons from experiences with the Coupled Model Intercomparison Project (CMIP) used by the IPCC Working Group I and II communities. We propose that the scientific community takes a more active role in curating the database around policy-relevant knowledge gaps, through an open and peer reviewed process of Model Intercomparison Projects (MIPs) supplemented with individual model studies. The database should be publicly accessible from the time of scenario submission, and actively involve a broad community in developing tools and analysing the database. These suggestions can broaden participation, increase transparency, and enhance the relevance of the database for users.

Abstract Xanthines such as caffeine and theobromine are among the most consumed psychoactive stimulants in the world, either as natural components of coffee, tea and chocolate, or as added ingredients. The present study assessed if xanthines affect liver sinusoidal endothelial cells (LSEC). Cultured primary rat LSEC were challenged with xanthines at concentrations typically obtained from normal consumption of xanthine-containing beverages, food or medicines; and at higher concentrations below the in vitro toxic limit. The fenestrated morphology of LSEC were examined with scanning electron and structured illumination microscopy. All xanthine challenges had no toxic effects on LSEC ultrastructure as judged by LSEC fenestration morphology, or function as determined by endocytosis studies. All xanthines in high concentrations (150 μg/mL) increased fenestration frequency but at physiologically relevant concentrations, only theobromine (8 μg/mL) showed an effect. LSEC porosity was influenced only by high caffeine doses which also shifted the fenestration distribution towards smaller pores. Moreover, a dose-dependent increase in fenestration number was observed after caffeine treatment. If these compounds induce similar changes in vivo, age-related reduction of LSEC porosity can be reversed by oral treatment with theobromine or with other xanthines using targeted delivery.

Despite being considered a normal flora, Providencia alcalifaciens can cause diarrhea. In a previous study, strain 2939/90, obtained from a diarrheal patient, caused invasion and actin condensation in mammalian cells, and diarrhea in a rabbit model. Four TnphoA mutants of 2939/90 produced negligible invasion and actin condensation in mammalian cells. Now, the parent strain and the mutants have been sequenced to locate TnphoA insertion sites and determine the effect on virulence. A TnphoA insertion was detected in the type three secretion system (T3SS) locus on a large plasmid and not in a T3SS locus on the chromosome. In 52 genomes of P. alcalifaciens surveyed, the chromosomal T3SS locus was present in all strains, including both P. alcalifaciens genomic clades, which we classified as group A and group B. Plasmid T3SS was present in 21 of 52 genomes, mostly in group A genomes, which included isolates from an outbreak of hemorrhagic diarrhea in dogs. The TnphoA insertion only in the plasmid T3SS locus affected the invasion phenotype, suggested that this locus is critical for causation of diarrhea. We conclude that a subgroup of P. alcalifaciens that possesses this plasmid-mediated T3SS is an enteric pathogen that can cause diarrheal disease.

There is growing interest in the potential of probiotics and other commensal dietary microbes to improve human health. This review will examine beer as a microbe-containing food and the considerations needed when using beer for probiotic and other live microbe delivery to the digestive tract. Although most beers harbor low numbers of live microbes after brewing is complete and the final product is an environmentally stressful environment which impairs long-term microbial survival, commercially-produced Lambic and sour beers can contain live microbes. Recent studies have also tested the viability and impacts of probiotic strains of Saccharomyces and lactobacilli strains in beer. The findings show there remains the need to adjust strain use and production practices to enable microbial growth and survival throughout the intended shelf-life. We discuss opportunities to increase microbial survival overall, as well as for strains that confer specific health benefits.

Valproate is the most effective treatment for idiopathic generalised epilepsy. Currently, its use is restricted in women of childbearing potential owing to high teratogenicity. Recent evidence extended this risk to men's offspring, prompting recommendations to restrict use in everybody aged

Abstract Background There are well‐recognized benefits of behavioral interventions that include exercise for children and adolescents with obesity. However, such behavioral weight management programs may precipitate unintended consequences. It is unclear if different exercise modalities impact eating behaviors differently in youth with obesity. Objectives The purpose of this study was to examine the effects of aerobic, resistance, and combined aerobic and resistance exercise training on eating attitudes and behaviors (uncontrolled eating, restrained eating, emotional eating, external eating and food craving) among adolescents with overweight and obesity. Methods N = 304 (70% female) adolescents with overweight and obesity participated in the 6‐month Healthy Eating Aerobic and Resistance Training in Youth (HEARTY) randomized controlled trial. All participants were inactive post‐pubertal adolescents (15.6 ± 1.4 years) with a mean BMI = 34.6 ± 4.5 kg/m2. The Food Craving Inventory (food cravings), Dutch Eating Behavior Questionnaire (restrained eating, emotional eating, external eating), and the Three‐Factor Eating Questionnaire (uncontrolled eating) were used to assess eating attitudes and behaviors. Results All exercise groups showed within‐group decreases in external eating and food cravings. Participants randomized to the Combined training group and were more adherent showed the greatest improvements in eating behaviors and cravings. Conclusions A 6‐month exercise intervention produced improvements in disordered eating behaviors and food cravings, but effects may be gender and modality‐specific. Findings highlight the need to tailor exercise intervention to participant characteristics for the promotion of healthier eating and weight management outcomes in youth with obesity. Clinical Trial Registration # and Date: ClinicalTrials.Gov NCT00195858, September 12, 2005

Abstract Anthropogenic emissions of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) have made significant contributions to global warming since the pre-industrial period and are therefore targeted in international climate policy. There is substantial interest in tracking and apportioning national contributions to climate change and informing equitable commitments to decarbonisation. Here, we introduce a new dataset of national contributions to global warming caused by historical emissions of carbon dioxide, methane, and nitrous oxide during the years 1851–2021, which are consistent with the latest findings of the IPCC. We calculate the global mean surface temperature response to historical emissions of the three gases, including recent refinements which account for the short atmospheric lifetime of CH4. We report national contributions to global warming resulting from emissions of each gas, including a disaggregation to fossil and land use sectors. This dataset will be updated annually as national emissions datasets are updated.

ABSTRACT Acinetobacter baumannii is a nosocomial multidrug-resistant pathogen that specifically colonizes and infects patients in intensive care units (ICUs). Genome plasticity of A. baumannii may contribute to the rapid development of A. baumannii resistance during patient treatment. There is little clarity on the dynamics of colonization of A. baumannii in humans. We studied 269 serial isolates of A. baumannii colonizing the rectum of 32 adult patients in an ICU; 5 to 16 isolates were obtained from each patient over a period of weeks to months. The isolates were sequenced using the Illumina platform. Multi-locus sequence typing revealed genetic diversity with 13 sequence types (STs); the dominant ST2 accounted for 202 of the 269 isolates and was isolated from each patient. A core genome comparison of isolates was used to elucidate a detailed understanding of the relationship among isolates within an ST and the genomic relationship among STs. One to three STs were observed in the isolates from each patient. Instances of unchanged colonization, sequential lineage colonization, and colonization with multiple lineages of A. baumannii were seen. The number of resistance genes carried by the isolates varied from 2 to 17. The predominant genes corresponded to those encoding resistance to β-lactam and aminoglycoside antibiotics. Generally, there was a strong correlation between ST and a particular antimicrobial resistance gene profile. This study makes an important baseline contribution to information that will help us understand the role of A. baumannii colonization in the development of opportunistic infections in ICU patients. IMPORTANCE Acinetobacter baumannii is a multidrug-resistant nosocomial pathogen that colonizes and infects debilitated patients in the ICU. There is very little information on the genomic characteristics of colonizing strains. This information is important to understand the evolution of lineages of A. baumannii that develop resistance while patients receive antibiotic treatment in the ICU. Our study demonstrated different patterns of colonization of the rectum of ICU patients with different STs of A. baumannii while one ST colonized all patients. Some STs carried more antibiotic resistance genes compared to others. However, there was a correlation between ST and a particular resistance gene profile. Our results further elucidate the dynamics of enteric colonization of this opportunistic pathogen.

ABSTRACTAmong the 16 two-component systems in the opportunistic human pathogen Staphylococcus aureus, only WalKR is essential. Like the orthologous systems in other Bacillota, S. aureus WalKR controls autolysins involved in peptidoglycan remodeling and is therefore intimately involved in cell division. However, despite the importance of WalKR in S. aureus, the basis for its essentiality is not understood and the regulon is poorly defined. Here, we defined a consensus WalR DNA-binding motif and the direct WalKR regulon by using functional genomics, including chromatin immunoprecipitation sequencing, with a panel of isogenic walKR mutants that had a spectrum of altered activities. Consistent with prior findings, the direct regulon includes multiple autolysin genes. However, this work also revealed that WalR directly regulates at least five essential genes involved in lipoteichoic acid synthesis (ltaS): translation (rplK), DNA compaction (hup), initiation of DNA replication (dnaA, hup) and purine nucleotide metabolism (prs). Thus, WalKR in S. aureus serves as a polyfunctional regulator that contributes to fundamental control over critical cell processes by coordinately linking cell wall homeostasis with purine biosynthesis, protein biosynthesis, and DNA replication. Our findings further address the essentiality of this locus and highlight the importance of WalKR as a bona fide target for novel anti-staphylococcal therapeutics.IMPORTANCEThe opportunistic human pathogen Staphylococcus aureus uses an array of protein sensing systems called two-component systems (TCS) to sense environmental signals and adapt its physiology in response by regulating different genes. This sensory network is key to S. aureus versatility and success as a pathogen. Here, we reveal for the first time the full extent of the regulatory network of WalKR, the only staphylococcal TCS that is indispensable for survival under laboratory conditions. We found that WalKR is a master regulator of cell growth, coordinating the expression of genes from multiple, fundamental S. aureus cellular processes, including those involved in maintaining cell wall metabolism, protein biosynthesis, nucleotide metabolism, and the initiation of DNA replication.

Abstract Clinical prediction models must be appropriately validated before they can be used. While validation studies are sometimes carefully designed to match an intended population/setting of the model, it is common for validation studies to take place with arbitrary datasets, chosen for convenience rather than relevance. We call estimating how well a model performs within the intended population/setting “targeted validation”. Use of this term sharpens the focus on the intended use of a model, which may increase the applicability of developed models, avoid misleading conclusions, and reduce research waste. It also exposes that external validation may not be required when the intended population for the model matches the population used to develop the model; here, a robust internal validation may be sufficient, especially if the development dataset was large.

Abstract Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxemia, which is associated with progressive loss of kidney function, where postprandial fluctuations in renal physiology may further compromise oxygen supply and kidney function. Therefore, we measured biomarkers of acute kidney injury (AKI) following a high‐fat meal with and without intermittent hypoxemia. Eighteen healthy young men (mean age [SD]: 22.7 years [3.1]) and seven middle‐aged to older individuals with OSA (54.4 years [6.4]) consumed a high‐fat meal during normoxia or intermittent hypoxemia (~15 hypoxic cycles per hour, ~85% oxyhemoglobin saturation) for 6 h. We observed no changes in estimated glomerular filtration rate and plasma concentrations of creatinine, neutrophil gelatinase‐associated lipocalin (NGAL), and kidney injury molecule‐1 (KIM‐1) at any measured time points. In both groups, plasma concentrations of interleukin‐18 (IL‐18) increased after 6 h during normoxia only (p = 0.033, ηp2 = 0.122), and plasma concentrations of liver‐type fatty acid‐binding protein (L‐FABP) transiently decreased after 3 h in both conditions (p = 0.008, ηp2 = 0.152). These findings indicate that AKI biomarkers are not acutely elevated during the postprandial state with or without intermittent hypoxemia, suggesting that other mechanisms may play more important roles in the progression of kidney disease in OSA.

Background:. Cytomegalovirus (CMV) infection causes significant morbidity and mortality in lung transplant recipients. Current guidelines use pretransplant donor and recipient CMV serostatus to predict the risk of subsequent CMV replication and length of antiviral prophylaxis. Immunological monitoring may better inform the risk of CMV infection in patients, thereby allowing for improved tailoring of antiviral prophylaxis. In this study, we compared 2 commercially available assays, the QuantiFERON-CMV (QFN-CMV) and T-Track-CMV (enzyme-linked immunosorbent spot assay), to predict the risk of CMV disease in lung transplant recipients. Methods:. We performed CMV immunity assays on 32 lung transplant recipients at risk of CMV disease as defined by serostatus (CMV-seropositive recipients, n = 26; or CMV-seronegative lung transplant recipient receiving a CMV-seropositive donor organ, n = 6). QFN-CMV and T-Track were performed on peripheral blood mononuclear cells, and episodes of CMV replication in both serum and bronchoalveolar lavage were found to be correlated to the CMV immune assays. The predictive ability of the assays was determined using Kaplan–Meier curves. Results:. There was a degree of concordance between tests, with 44% of recipients positive for both tests and 28% negative for both tests; however, test results were discordant in 28% of cases. A negative result in either the QFN-CMV (P < 0.01) or T-Track (P < 0.05) assays was obtained in a significantly higher number of recipients who experienced CMV replication in the blood. Using these assays together gave higher predictability of CMV replication, with only 1 recipient experiencing CMV replication in the blood who obtained a positive test result for both assays. Neither assay was able to predict recipients who experienced CMV replication in the lung allograft. Conclusions:. Our study demonstrates that CMV immunity assays can predict viremia; however, the lack of association with allograft infection suggests that CMV-specific T-cell immunity in the circulation is not associated with the control of CMV replication within the transplanted lung allograft.

Aspergillus fumigatus can cause different clinical manifestations/phenotypes in lung transplant (LTx) recipients and patients with chronic respiratory diseases. It can also precipitate chronic lung allograft dysfunction (CLAD) in LTx recipients. Many host factors have been linked with the severity of A. fumigatus infection, but little is known about the contribution of different A. fumigatus strains to the development of different phenotypes and CLAD. We used multi-locus microsatellite typing (MLMT) to determine if there is a relationship between strain (i.e., genotype) and phenotype in 60 patients post LTx or with chronic respiratory disease across two time periods (1 November 2006–31 March 2009 and 1 November 2015–30 June 2017). The MLMT (STRAf) assay was highly discriminatory (Simpson’s diversity index of 0.9819–0.9942) with no dominant strain detected. No specific genotype–phenotype link was detected, but several clusters and related strains were associated with invasive aspergillosis (IA) and colonisation in the absence of CLAD. Host factors were linked to clinical phenotypes, with prior lymphopenia significantly more common in IA cases as compared with A. fumigatus-colonised patients (12/16 [75%] vs. 13/36 [36.1%]; p = 0.01), and prior Staphylococcus aureus infection was a significant risk factor for the development of IA (odds ratio 13.8; 95% confidence interval [2.01–279.23]). A trend toward a greater incidence of CMV reactivation post-A. fumigatus isolation was observed (0 vs. 5; p = 0.06) in LTx recipients. Further research is required to determine the pathogenicity and immunogenicity of specific A. fumigatus strains.

A rapid phase-out of unabated coal use is essential to limit global warming to below 2 °C. This review presents a comprehensive assessment of coal transitions in mitigation scenarios consistent with the Paris Agreement, using data from more than 1500 publicly available scenarios generated by more than 30 integrated assessment models. Our ensemble analysis uses clustering techniques to categorize coal transition pathways in models and bridges evidence on technological learning and innovation with historical data of energy systems. Six key findings emerge: First, we identify three archetypal coal transitions within Paris-consistent mitigation pathways. About 38% of scenarios are ‘coal phase out’ trajectories and rapidly reduce coal consumption to near zero. ‘Coal persistence’ pathways (42%) reduce coal consumption much more gradually and incompletely. The remaining 20% follow ‘coal resurgence’ pathways, characterized by increased coal consumption in the second half of the century. Second, coal persistence and resurgence archetypes rely on the widespread availability and rapid scale-up of carbon capture and storage technology (CCS). Third, coal-transition archetypes spread across all levels of climate policy ambition and scenario cycles, reflecting their dependence on model structures and assumptions. Fourth, most baseline scenarios—including the shared socio-economic pathways (SSPs)—show much higher coal dependency compared to historical observations over the last 60 years. Fifth, coal-transition scenarios consistently incorporate very optimistic assumptions about the cost and scalability of CCS technologies, while being pessimistic about the cost and scalability of renewable energy technologies. Sixth, evaluation against coal-dependent baseline scenarios suggests that many mitigation scenarios overestimate the technical difficulty and costs of coal phase-outs. To improve future research, we recommend using up-to-date cost data and evidence about innovation and diffusion dynamics of different groups of zero or low-carbon technologies. Revised SSP quantifications need to incorporate projected technology learning and consistent cost structures, while reflecting recent trends in coal consumption.

Carbon dioxide removal (CDR) is expected to play a critical role in reaching net zero CO _2 and especially net zero greenhouse gase (GHG) emissions. However, the extent to which the role of CDR in counterbalancing residual emissions can be reduced has not yet been fully quantified. Here, we use a state-of-the-art integrated assessment model to develop a ‘Maximum Sectoral Effort’ scenario which features global emissions policies alongside ambitious effort across sectors to reduce their gross GHG emissions and thereby the CDR required for offsets. We find that these efforts can reduce CDR by over 50% globally, increase both the relative and absolute role of the land sink in storing carbon, and more evenly distribute CDR contributions and associated side-effects across regions compared to CO _2 pricing alone. Furthermore, the lower cumulative CO _2 and nonCO _2 emissions leads to earlier and lower peak temperatures. Emphasizing reductions in gross, in addition to net emissions while disallowing the substitution of less durable CDR for offsets can therefore reduce both physical and transition risks associated with high CDR deployment and temperature overshoot.

Abstract Correlation between structural data from optical coherence tomography and functional data from the visual field may be suboptimal because of poor mapping of OCT measurement locations to VF stimuli. We tested the hypothesis that stronger structure–function correlations in the macula can be achieved with fundus-tracking perimetery, by precisely mapping OCT measurements to VF sensitivity at the same location. The conventional 64 superpixel (3° × 3°) OCT grid was mapped to VF sensitivities averaged in 40 corresponding VF units with standard automated perimetry (conventional mapped approach, CMA) in 38 glaucoma patients and 10 healthy subjects. Similarly, a 144 superpixel (2° × 2°) OCT grid was mapped to each of the 68 locations with fundus-tracking perimetry (localized mapped approach, LMA). For each approach, the correlation between sensitivity at each VF unit and OCT superpixel was computed. Vector maps showing the maximum correlation between each VF unit and OCT pixel was generated. CMA yielded significantly higher structure–function correlations compared to LMA. Only 20% of the vectors with CMA and

Cereal grains have been domesticated largely from food grains to feed and malting grains. Barley (Hordeum vulgare L.) remains unparalleled in its success as a primary brewing grain. However, there is renewed interest in “alternative” grains for brewing (and distilling) due to attention being placed on flavor, quality, and health (i.e., gluten issues) aspects that they may offer. This review covers basic and general information on “alternative grains” for malting and brewing, as well as an in-depth look at several major biochemical aspects of these grains including starch, protein, polyphenols, and lipids. These traits are described in terms of their effects on processing and flavor, as well as the prospects for improvement through breeding. These aspects have been studied extensively in barley, but little is known about the functional properties in other crops for malting and brewing. In addition, the complex nature of malting and brewing produces a large number of brewing targets but requires extensive processing, laboratory analysis, and accompanying sensory analysis. However, if a better understanding of the potential of alternative crops that can be used in malting and brewing is needed, then significantly more research is required.