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OBJECTIVE: To summarize 10 high-quality medical articles published in 2022 that are relevant to primary care physicians. SELECTING THE EVIDENCE: Routine surveillance of tables of contents in relevant medical journals and EvidenceAlerts was conducted by the PEER (Patients, Experience, Evidence, Research) team, a group of primary care health care professionals with an interest in evidence-based medicine. Articles were selected and ranked based on relevance to practice. MAIN MESSAGE: Published articles from 2022 most likely to influence primary care practice examined the following subjects: reducing dietary sodium for heart failure; timing of blood pressure medications to reduce cardiovascular outcomes; adding as-needed corticosteroids to rescue puffers for asthma exacerbations; influenza vaccination after myocardial infarction; comparing various medications for diabetes management; tirzepatide for weight loss; low FODMAP diet for irritable bowel syndrome; prune juice for constipation; impact of regular acetaminophen use on patients with hypertension; and time required to care for patients in primary care. Two “honourable mention” studies are also summarized. CONCLUSION: Research published in 2022 yielded several high-quality articles on various conditions relevant to primary care, including hypertension, heart failure, asthma, and diabetes.

In this case series, we present five cases of pregnant women who sought medical attention for reduced fetal movements with an ongoing mild maternal Covid-19 infection at a Stockholm hospital in Spring of 2021. At the time of admission, the patients were in gestational week between 24 + 0 and 33 + 5 . Abdominal ultrasound at the hospital showed no fetal movements, and cardiotocography (CTG) was pathological. All women delivered via cesarean section within 24 hours after admission. Placental pathology in all cases showed massive perivillous fibrin deposition and extensive histiocytic intervillositis. All placentas were Covid-19 polymerase chain reaction (PCR) positive. The infants were Covid-19 PCR negative. Consistent with other published case reports, we hypothesize that Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect the placenta resulting in massive perivillous fibrin deposition and histiocytic intervillositis leading to acute placental insufficiency and fetal hypoxia. The absence of intrauterine growth restriction also augments the theory of an acute onset of placental insufficiency due to the Covid-19 infection.

This chapter updates the COVID-19 chapter from the 2020 Annual Data Report with trends through February 12, 2022, and introduces trends in COVID-19-specific cause of death on the waiting list and posttransplant. Transplant rates remain at or above prepandemic levels for all organs, indicating a sustained transplantation system recovery following the initial 3-month disruption due to the onset of the pandemic. Posttransplant mortality and graft failure remain a concern in all organs, with rates surging corresponding to waves of the pandemic. Waitlist mortality due to COVID-19 is also a concern, particularly among kidney candidates. While the recovery of the transplantation system has been sustained in the second year of the pandemic, ongoing efforts should focus on reducing posttransplant and waitlist mortality due to COVID-19, and graft failure.

Lung clearance index (LCI) is the most used outcome from the multiple-breath washout test. As known for decades, the LCI is not linearly related to dead space ventilation, giving difficulties interpreting changes over time and in clinical trials. We present a new and improved outcome based on LCI, the ventilation distribution efficiency (VDE), which solves this problem by being linearly related to dead space ventilation. A pediatric age range reference equation for VDE is presented.

Long-term treatment with inhaled antibiotics is recommended for people with cystic fibrosis (pwCF) chronically infected with Pseudomonas aeruginosa (PA). However, pwCF without chronic PA infection are also commonly treated with inhaled antibiotics. Using data from the European Cystic Fibrosis Patient Registry (ECFSPR) we aimed to determine the prevalence and factors associated with inhaled antibiotic treatment in pwCF without chronic PA infection, and long-term outcomes with inhaled antibiotics use.The ECFSPR was searched for pwCF 6 years of age and older who were not chronically infected with PA at baseline. Factors associated with inhaled antibiotic use were first assessed through a logistic regression. From this model a propensity score was computed for each individual, providing the likelihood of being treated with inhaled antibiotics. Long-term outcomes with and without inhaled antibiotics were assessed separately for propensity scores tertiles.7210 pwCF without chronic PA infection at baseline were included, with 2722 (37.75%) receiving long-term treatment with inhaled antibiotics. Treatment with inhaled antibiotics was more prevalent with severe genotype, diabetes, pancreatic insufficiency, and past infection with chronic PA (OR 3.8, 95% CI, 2.88-5.04). Treatment with inhaled antibiotics was not associated with a reduced risk for acquisition of PA or other resistant pathogens, or with improved lung function decline, mortality, or transplantation.Many pwCF without chronic PA infection are receiving long-term treatment with inhaled antibiotics despite lack of support from clinical trials or practice guidelines. We did not observe improve outcomes with inhaled antibiotics. Our findings suggest controlled studies evaluating specific inhaled antibiotic regimens targeting specific pathogens or indications be performed to determine their effect.

Electroconvulsive therapy (ECT) is used to treat severe psychiatric disorders and is associated with reduced risk of suicide and all-cause mortality in patients with severe depression. We investigated the causes of death occurring shortly after ECT and identified potential risk factors for medical causes of death.Patients treated with ECT between 2012 and 2018 were included in this Swedish register-based study. Multivariate binary logistic regression was used to calculate odds ratios for covariates to determine potential predictors of 30-day mortality.Of the 20,225 included patients, 93 (0.46 %) died of suicide and 123 (0.61 %) died of medical causes after ECT. Cardiovascular disease was the most common medical cause of death (n = 49, 40 %). An older age, a Charlson Comorbidity Index of 1 or more, atrial fibrillation, kidney disease, reflux disease, dementia, and cancer were associated with increased risk of death by medical causes.Real-life observational studies based on registry data may demonstrate associations, but cannot determine causality. If medical records had been available, we would be better able to determine if deaths were due to the ECT, anesthesia, pre-existing medical conditions, or the mental disorder.ECT appears to be a low-risk medical procedure. Older individuals with severe somatic diseases have the highest risk of death and extra measures should be considered to optimize their medical health during the pre-ECT workup, and during and after ECT.

To what extent did the Covid-19 pandemic affect the tools, priorities and organisation of cultural policies? And did the pandemic enhance the digital aspect of these policies? This paper compares pandemic cultural policy measures in seven European countries to answer these questions. The countries all installed a plurality of mitigating measures, combining grants and subsidies, compensation of lost income, income support and financial flexibility, creating a tendency towards cultural policy turning into economic policy, fiscal policy, and labour market policy. Cultural policies have not been fundamentally challenged by the pandemic, in the sense that it has affected the essential political tools, divisions of labour, or core goals. The responses have confirmed an existing policy structure or enhanced existing developments. The importance of a state-centred or a federalist cultural policy system has not been challenged in a substantial way. Secondly there is little evidence to show a general acceleration of national digital cultural policies.

OBJECTIVE: To describe the course of the outbreak and infection control measures to stop the spread of sequence type 15 OXA-23-producing Acinetobacter baumannii in the Burn Center of Uppsala University Hospital, between November 2014 and the end of April 2015. METHODS: Compliance with hand hygiene, dress code, and cleaning routines were reviewed, the ward's environment was systematically investigated to identify potential environmental sources. Sampling routines for A. baumannii, from patients and environment, were established, and the epidemiological relationship was analysed for all carbapenem-resistant A. baumannii isolates using arbitrarily primed polymerase chain reaction (AP-PCR) and pulsed-field gel electrophoresis (PFGE). RESULTS: A total of 54 patients were treated at the burn intensive care unit during the studied, approximately five months period, and an OXA-23-producing A. baumannii was isolated from nine patients (9/54, 17%), whereof two died (2/9, 22.2%). All isolates shared identical PFGE-genotype patterns and belonged to sequence type 15; AP-PCR was eligible for prompt epidemiological investigations. CONCLUSIONS: Higher awareness and increased compliance with hand hygiene and dress code as well as intensified cleaning protocols of the environment and equipment were successfully established and likely to have led to stop the spread of sequence type 15 OXA-23-producing Acinetobacter baumannii.

Background Despite its negative impact on patients and nurses, the use of restraint in somatic health care continues in many settings. Understanding the reasons and justifications for the use of restraint among nurses is crucial in order to manage this challenge. Aim To understand nurses’ justifications for restraint use in neurosurgical care. Research design A qualitative, descriptive design was used. Data were analysed with inductive qualitative content analysis. Participants and research context Semi-structured interviews with 15 nurses working in three neurosurgical departments in Sweden. Ethical considerations Approved by The Regional Ethics Committee, Stockholm, Sweden. Findings The analysis resulted in three categories. The category Patient factors influencing restraint use describes patient factors that trigger restraint, such as a diminished decision-making competence, restlessness, and need for invasive devices. The category Specific reasons for justifying restraint describes reasons for restraining patients, such as restraint being used for the sake of the patient or for the sake of others. The category General reasoning in justifying restraint describes how nurses reason when using restraint, and the decision to use restraint was often based on a consequentialist approach where the nurses’ weighed the pros and cons of different alternatives. Discussion Nurses with experience of restraint use were engaged in a constant process of justifying and balancing different options and actions. Restraint was considered legitimate if the benefit exceeded the suffering, but decisions on which restraint measures to use and when to use them depended on the values of the individual nurse. Conclusion How nurses reason when justifying restraint, why they use restraint, and who they use restraint on must be considered when creating programs and guidelines to reduce the use of restraint and to ensure that when it is used it is used carefully, appropriately, and with respect.

Background Delayed gastric conduit emptying can occur after esophagectomy and has been shown to be associated with increased risk for postoperative complications. Application of a standardized clinical protocol after esophagectomy including an upper gastrointestinal contrast study has the potential to improve postoperative outcomes. Methods Prospective cohort including all patients operated with esophagectomy at two high-volume centers for esophageal surgery. The standardized clinical protocol included an upper gastrointestinal contrast study on day 2 or 3 after surgery. All images were compiled and evaluated for the purpose of the study. Clinical data was collected in IRB approved institutional databases at the participating centers. Results The study included 119 patients treated with esophagectomy of whom 112 (94.1%) completed an upper gastrointestinal contrast study. The results showed that 8 (7.1%) patients had radiological delayed gastric conduit emptying defined as no emptying of contrast through the pylorus. Partial conduit emptying was seen in 34 (30.4%) patients, and 70 (62.5%) patients had complete conduit emptying. Complete or partial emptying was associated with significantly earlier nasogastric tube removal (3 vs. 6 days) and hospital discharge 8 vs. 17 days, P Conclusion The results of the study demonstrate that postoperative upper gastrointestinal contrast studies can be used to assess the level of emptying of the gastric conduit after esophagectomy. Application of upper gastrointestinal contrast study in the ERAS guidelines-driven standardized clinical pathway after esophagectomy has the potential to improve postoperative outcomes.

Two specimens of Borealosuchus collected from the lower facies of the Ravenscrag Formation (earliest Paleocene) in southern Saskatchewan are described. One largely complete individual featuring a partial skull, mandible, and postcrania can be unambiguously assigned to Borealosuchus griffithi Wu et al. 2001 a. The other specimen consisting of skull and partial postcranial fragments is referred to Borealosuchus sternbergii Gilmore, 1910 based on diagnostic cranial features. These specimens confirm the earliest occurrence of this clade in the province of Saskatchewan and expand the known stratigraphic and geographic range of their respective species. The discovery of Borealosuchus griffithi and Borealosuchus sternbergii in proximity to each other within the same deposits suggests temporal and spatial range overlap in the Big Muddy area during the earliest Paleocene, hinting at possible niche partitioning or other ecological relationships between members of the same genus.

This study is based on an interest in interaction between science and society and how this structures science and society in tandem. In order to capture such interaction, we are analysing statements in scientific publications. The purpose of this study is to analyse relevancing in scientific publications by studying who are addressed by the research contributions and why these are considered to be relevant. Our case is the field of research labelled as International Large-Scale Assessments (ILSA), such as the OECD's Programme for International Student Assessment (PISA), created to analyse relations between educational designs and student performances. We identified a large set of research publications by means of the search engines Web of Science and Scopus. We selected publications that were peer reviewed and based on empirical comparisons between at least two countries. A large majority were only analysing student achievement, and few were researching impacts of educational variations. Relevance statements were mostly addressing policymakers. These findings are indicating strong social structuring of much ILSA research., Este estudio se basa en un interés por la interacción entre ciencia y sociedad y cómo esto estructura la ciencia y la sociedad en conjunto. Para capturar tal interacción, analizamos declaraciones en publicaciones científicas. El propósito de este estudio es analizar relevancing en las publicaciones científicas estudiando a quiénes se dirigen las contribuciones de investigación y por qué se consideran relevantes. Nuestro caso es el campo de investigación denominado ILSA - Evaluaciones Internacionales a Gran Escala, como el Programa para la Evaluación Internacional de Alumnos (PISA) de la OCDE, diseñado para analizar las relaciones entre los modelos educativos y el desempeño de los estudiantes. Identificamos un gran conjunto de publicaciones de investigación a través de los motores de búsqueda Web of Science y Scopus. Seleccionamos publicaciones revisadas por pares y basadas en comparaciones empíricas entre al menos dos países. Una gran mayoría solo analizaba el rendimiento de los estudiantes, y pocos investigaban los impactos de las variaciones educativas. Las reivindicaciones de relevancia se dirigieron sobre todo a los responsables políticos. Estos hallazgos indican una fuerte estructuración social de gran parte de la investigación de ILSA., Este estudo tem por base um interesse na interação entre ciência e sociedade e como isto estrutura a ciência e a sociedade em conjunto. De modo a captar tais interações, analisamos afirmações em publicações científicas. A finalidade deste estudo consiste em analisar o relevancing em publicações científicas através da análise dos destinatários a quem os contributos da investigação são endereçados e porque estes são considerados relevantes. O nosso caso é a área de investigação chamada ILSA – Avaliações Internacionais em Grande Escala, como o Programa Internacional de Avaliação de Alunos (PISA) da OCDE, concebido para analisar as relações entre modelos educativos e desempenhos dos estudantes. Identificámos um grande grupo de publicações de investigações através dos motores de busca Web of Science e Scopus. Selecionámos publicações revistas por pares e baseadas em comparações empíricas entre pelo menos dois países. Uma grande maioria analisava apenas o aproveitamento dos alunos, havendo poucos a investigar os impactos de variações educativas. As afirmações de relevância eram endereçadas acima de tudo aos decisores políticos. Estes resultados indicam uma estruturação social forte de grande parte da investigação ILSA.

This study is based on an interest in interaction between science and society and how this structures science and society in tandem. In order to capture such interaction, we are analysing statements in scientific publications. The purpose of this study is to analyse relevancing in scientific publications by studying who are addressed by the research contributions and why these are considered to be relevant. Our case is the field of research labelled as International Large-Scale Assessments (ILSA), such as the OECD's Programme for International Student Assessment (PISA), created to analyse relations between educational designs and student performances. We identified a large set of research publications by means of the search engines Web of Science and Scopus. We selected publications that were peer reviewed and based on empirical comparisons between at least two countries. A large majority were only analysing student achievement, and few were researching impacts of educational variations. Relevance statements were mostly addressing policymakers. These findings are indicating strong social structuring of much ILSA research., Sisyphus — Journal of Education, Vol. 11 No. 2 (2023): Thinking Education in Times of Transition

Research topic: One Health Surveillance in Practice: Experiences of Integration among Human Health, Animal Health, Environmental Health, and Food Safety Sectors; International audience; Introduction The awareness of scientists and policy makers regarding the requirement for an integrated One Health (OH) approach in responding to zoonoses has increased in recent years. However, there remains an overall inertia in relation to the implementation of practical cross-sector collaborations. Foodborne outbreaks of zoonotic diseases continue to affect the European population despite stringent regulations, evidencing the requirement for better ‘prevent, detect and response’ strategies. Response exercises play an essential role in the improvement of crisis management plans, providing the opportunity to test practical intervention methodologies in a controlled environment. Methods The One Health European Joint Programme simulation exercise (OHEJP SimEx) aimed at practicing the OH capacity and interoperability across public health, animal health and food safety sectors in a challenging outbreak scenario. The OHEJP SimEx was delivered through a sequence of scripts covering the different stages of a Salmonella outbreak investigation at a national level, involving both the human food chain and the raw pet feed industry. Results A total of 255 participants from 11 European countries (Belgium, Denmark, Estonia, Finland, France, Italy, Norway, Poland, Portugal, Sweden, the Netherlands) took part in national level two-day exercises during 2022. National evaluations identified common recommendations to countries aiming to improve their OH structure to establish formal communication channels between sectors, implement a common data sharing platform, harmonize laboratory procedures, and reinforce inter-laboratory networks within countries. The large proportion of participants (94%) indicated significant interest in pursuing a OH approach and desire to work more closely with other sectors. Discussion The OHEJP SimEx outcomes will assist policy makers in implementing a harmonized approach to cross-sector health-related topics, by highlighting the benefits of cooperation, identifying gaps in the current strategies and suggesting actions required to better address foodborne outbreaks. Furthermore, we summarize recommendations for future OH simulation exercises, which are essential to continually test, challenge and improve national OH strategies.

In this paper, we use Large Eddy Simulations (LES) in combination with the Ffowcs Williams - Hawkings method to study the influence of chevrons on the flow field as well as the noise produced by a closely installed M = 0.6 jet. The LES simulations are performed with the spectral/hp element framework Nektar++. Nektar++ uses the high-order discontinuous Galerkin method and an implicit scheme based on the matrix-free Newton-GMRES method to discretize the unfiltered Navier-Stokes equations in space and time, respectively. The far-field noise is computed using Antares. Antares solves the Ffowcs Williams - Hawkings equation for a permeable integration surface in the time-domain using a source-time dominant algorithm. The aerodynamic results show good agreement with experimental data obtained in the Doak Laboratory Flight Jet Rig, located at the University of Southampton. Some discrepancies are observed in terms of the far-field noise levels, especially for higher polar observer angles relative to the downstream jet axis. In terms of noise reduction potential, the simulations predict that the chevrons reduce the OASPL by 1dB compared to an installed round nozzle for all observers located on the unshielded side of the wing. This should be compared to the experiments, which predict a 1.5dB noise reduction for the same chevron nozzle.

The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterise the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified following human TBI. iPSC-derived microglia were exposed to IL-1β, IL-4, IL-6, IL-10 and TNF in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72-hour time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1β (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses to our previous studies of iPSC-derived neuronal and astrocyte cultures and the in-vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, as compared to astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.

Plasmonic systems effectively convert light into electrical charges and heat, which can mediate catalytic transformations. There are many examples of plasmonic photothermal catalytic reactions, but the involvement of hot carriers in the catalytic process remains a matter of intense debate and controversy. Here, we demonstrate the direct use of plasmon hot electrons in the photoelectrocatalytic CO2 reduction with visible light. A purposely assembled plasmonic nanohybrid system consisting of NiO/Au/ReI(phen-NH2)(CO)3Cl (phen-NH2 = 10-Phenanthrolin-5-amine) enabled direct access into hot-carrier-mediated reaction pathways by ultrafast spectroscopy, electrochemistry and catalytic testing. The ReI(phen-NH2)(CO)3Cl complex decomposes above 305°C, limiting thermal CO2 reduction contribution, making the plasmonic hot carriers the prime culprit for the process. Plasmonic light activation of CO2 provides a sustainable route for producing carbon fuels and feedstocks for society.

The growing use of photosynthetic microorganisms for food and food-related applications is driving related biotechnology research forward. Increasing consumer acceptance, high sustain-ability, demand of eco-friendly sources for food, and considerable global economic concern are among the main factors to enhance the focus on the novel foods. In the cases of not toxic strains, photosynthetic microorganisms not only provide a source of sustainable nutrients but are also potentially healthy. Several published studies showed that microalgae are sources of accessible protein and fatty acids. More than 400 manuscripts were published per year in the last 4 years. Furthermore, industrial approaches utilizing these microorganisms are resulting in new jobs and services. This is in line with the global strategy for bioeconomy that aims to support sustainable development of bio-based sectors. Despite the recognized potential of the microalgal biomass value chain, significant knowledge gaps still exist especially regarding their optimized production and utilization. This review highlights the potential of microalgae and cyanobacteria for food and food-related applications as well as their market size. The chosen topics also include advanced production as mixed microbial communities, production of high-value biomolecules, photopro-duction of terpenoid flavoring compounds, their utilization for sustainable agriculture, applica-tion as source of nutrients in space, and a comparison with heterotrophic microorganisms like yeast to better evaluate their advantages over existing nutrient sources. This comprehensive assessment should stimulate further interest in this highly relevant research topic.

Objective: To examine the association between surgical waiting times (SWTs) and all-cause mortality (ACM) in non-metastatic patients with RCC, in relation to tumour stage. Patients and methods: This nation-wide population-based cohort study included 9,918 M0 RCC patients registered in the National Swedish Kidney Cancer Register, between 2009 and 2021, followed-up for ACM until 9 December 2021, and having measured SWTs. The associations between primarily SWTs from date of radiological diagnosis to date of surgery (WRS) and secondarily SWTs from date of radiological diagnosis to date of treatment decision (WRT) and date of treatment decision to date of surgery (WTS), in relation to ACM, were analysed using Cox regression analysis, adjusted for clinical and demographic characteristics, stratified and unstratified according to T-stage. Results: During a mean follow-up time of 5 years (49,873 person-years), 23% (n = 2291) of the patients died. The adjusted hazard ratio (AHR) for WRS (months) for all patients was 1.03 (95% confidence interval [CI] = 1.02–1.04; p < 0.001). When subdividing WRS on T-stage, the AHRs were 1.03 (95% CI = 1.01–1.04; p < 0.001) and 1.05 (95% CI = 1.02–1.08; p = 0.003) for stages T1 and T3, respectively, while non-significant for T2 (p = 0.079) and T4 (p = 0.807). Similar results were obtained for WRT and WTS. Conclusions: Prolonged SWTs significantly increased the risk of early overall death among patients with RCC. The increased risk of early death from any cause show the importance of shortening SWTs in clinical work of patients with this malignant disease.

Background: We previously observed decreasing resection rates of non-metastatic gastric adenocarcinoma (GaC) in the US and some European countries. If and to what extent these trends affect the trends in overall survival (OS) of patients with non-metastatic GaC at the population level remain unclear. This large international population-based cohort study aimed to assess the impact of the previously observed decreasing resection rates on multivariable-adjusted trends in the long-term OS of patients with non-metastatic GaC. Methods: Individual-level data of patients with non-metastatic GaC were obtained from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, and Slovenia, and the US Surveillance, Epidemiology, and End Results database. We analyzed data for each country separately. Associations between year of diagnosis and OS were assessed using Cox proportional hazards regression model with adjustment for multiple prognostic variables, with and without including resection and chemotherapy as potential explanatory variables. Results: A total of 66,398 non-metastatic GaC patients diagnosed in 2003-2016 were analyzed, with an accumulated follow-up of 172,357 person-years. Without adjustment for resection, OS was improved only slightly in the US [hazard ratio (HR) per year = 0.99; HR ≥ vs. = 0.96], and no improvement was observed in the investigated European countries, with OS even worsening in Sweden (HR per year = 1.03; HR ≥ vs. = 1.17). After adjusting for resection, the increasing OS trend became stronger in the US (HR per year = 0.98; HR ≥ vs. = 0.88), and the temporal trend became insignificant in Sweden. In Slovenia (HR per year = 0.99; HR ≥ vs. = 0.92) and Norway (HR per year = 0.97; HR ≥ vs. = 0.86), improved OS over time emerged after resection adjustment. Improved OS in patients undergoing resection was observed in the US, the Netherlands, and Norway. Adjustment for chemotherapy did not alter the observed associations. Stratified analyses by tumor location showed mostly similar results with the findings in all patients with non-metastatic GaCs regarding the associations between year of diagnosis and survival. Conclusions: OS of patients with non-metastatic GaC mostly did not improve in selected European countries and was even worsened in Sweden, while it was slightly increased in the US in the early 21 st century. Progress in OS of patients with non-metastatic GaC seems to have been impeded to a large extent by decreasing rates of resection.

OBJECTIF: Faire la synthèse de 10 articles médicaux de grande qualité, publiés en 2022, qui présentent un intérêt manifeste pour les médecins de soins primaires. SÉLECTION DES DONNÉES PROBANTES: L’équipe du groupe PEER (Patients, Expérience, Évidence, Recherche), formée de professionnels des soins primaires qui s’intéressent à la médecine fondée sur des données probantes, a effectué une surveillance systématique des tables des matières dans des revues médicales pertinentes et dans EvidenceAlerts. MESSAGE PRINCIPAL: Les articles publiés en 2022 qui étaient les plus susceptibles d’influer sur la pratique des soins primaires examinaient les sujets suivants : la réduction du sodium alimentaire pour l’insuffisance cardiaque; la chronologie des médicaments antihypertenseurs pour réduire les paramètres cardiovasculaires; l’ajout, au besoin, de corticostéroïdes aux inhalateurs de secours pour les exacerbations de l’asthme; la vaccination contre la grippe après un infarctus du myocarde; une comparaison de divers médicaments pour le contrôle du diabète; le tirzépatide pour la perte pondérale; les régimes faibles en FODMAP pour le syndrome du côlon irritable; le jus de pruneaux pour la constipation; l’impact d’un usage régulier d’acétaminophène sur les patients hypertendus; le temps requis pour les soins aux patients en soins primaires. Deux études « avec mention honorable » ont aussi été résumées. CONCLUSION: La recherche publiée en 2022 a produit plusieurs articles de grande qualité sur divers problèmes d’intérêt en soins primaires, dont l’hypertension, l’insuffisance cardiaque, l’asthme et le diabète.

Funding: This project was supported by the National Science Foundation (grant numbers DEB 1838283 and IOS 2032006 to D.M.-S. and Dav.R. and DEB 1838273 and DGE 1633299 to L.D.), National Institutes of Health (grant numbers R01HG002939 and U24HG010136 to J.S., R.H., A.F.A.S., and Je.R.), NHGRI (grant number R01HG008742 to Z.C.), Irish Research Council (grant number IRCLA/ 2017/58 to E.T.), Science Foundation Ireland (grant number 19/FFP/6790 to E.T.), Max Planck Research Group awarded by the Max Planck Gesellschaft to S.V., Human Frontiers Science Program (grant number RGP0058/2016 to S.V.), UK Research and Innovation (grant number MR/T021985/1 to S.V.), and the Swedish Research Council Distinguished Professor Award to K.L.-T. Horizontal transfer of transposable elements (TEs) is an important mechanism contributing to genetic diversity and innovation. Bats (order Chiroptera) have repeatedly been shown to experience horizontal transfer of TEs at what appears to be a high rate compared with other mammals. We investigated the occurrence of horizontally transferred (HT) DNA transposons involving bats. We found over 200 putative HT elements within bats; 16 transposons were shared across distantly related mammalian clades, and 2 other elements were shared with a fish and two lizard species. Our results indicate that bats are a hotspot for horizontal transfer of DNA transposons. These events broadly coincide with the diversification of several bat clades, supporting the hypothesis that DNA transposon invasions have contributed to genetic diversification of bats. Publisher PDF

Annotating coding genes and inferring orthologs are two classical challenges in genomics and evolutionary biology that have traditionally been approached separately, limiting scalability. We present TOGA, a method that integrates structural gene annotation and orthology inference. TOGA implements a different paradigm to infer orthologous loci, improves ortholog detection and annotation of conserved genes compared to state-of-the-art methods, and handles even highly-fragmented assemblies. TOGA scales to hundreds of genomes, which we demonstrate by applying it to 488 placental mammal and 501 bird assemblies, creating the largest comparative gene resources so far. Additionally, TOGA detects gene losses, enables selection screens, and automatically provides a superior measure of mammalian genome quality. Together, TOGA is a powerful and scalable method to annotate and compare genes in the genomic era.

INTRODUCTION: Thousands of genetic variants have been associated with human diseases and traits through genome-wide association studies (GWASs). Translating these discoveries into improved therapeutics requires discerning which variants among hundreds of candidates are causally related to disease risk. To date, only a handful of causal variants have been confirmed. Here, we leverage 100 million years of mammalian evolution to address this major challenge. RATIONALE: We compared genomes from hundreds of mammals and identified bases with unusually few variants (evolutionarily constrained). Constraint is a measure of functional importance that is agnostic to cell type or developmental stage. It can be applied to investigate any heritable disease or trait and is complementary to resources using cell type– and time point–specific functional assays like Encyclopedia of DNA Elements (ENCODE) and Genotype-Tissue Expression (GTEx). RESULTS: Using constraint calculated across placental mammals, 3.3% of bases in the human genome are significantly constrained, including 57.6% of coding bases. Most constrained bases (80.7%) are noncoding. Common variants (allele frequency ≥ 5%) and low-frequency variants (0.5% ≤ allele frequency < 5%) are depleted for constrained bases (1.85 versus 3.26% expected by chance, P < 2.2 × 10(−308)).Pathogenic ClinVar variants are more constrained than benign variants (P < 2.2 × 10(−16)). The most constrained common variants are more enriched for disease single-nucleotide polymorphism (SNP)–heritability in 63 independent GWASs. The enrichment of SNP-heritability in constrained regions is greater (7.8-fold) than previously reported in mammals and is even higher in primates (11.1-fold). It exceeds the enrichment of SNP-heritability in nonsynonymous coding variants (7.2-fold) and fine-mapped expression quantitative trait loci (eQTL)–SNPs (4.8-fold). The enrichment peaks near constrained bases, with a log-linear decrease of SNP-heritability enrichment as a function of the distance to a constrained base. Zoonomia constraint scores improve functionally informed fine-mapping. Variants at sites constrained in mammals and primates have greater posterior inclusion probabilities and higher per-SNP contributions. In addition, using both constraint and functional annotations improves polygenic risk score accuracy across a range of traits. Finally, incorporating constraint information into the analysis of noncoding somatic variants in medulloblastomas identifies new candidate driver genes. CONCLUSION: Genome-wide measures of evolutionary constraint can help discern which variants are functionally important. This information may accelerate the translation of genomic discoveries into the biological, clinical, and therapeutic knowledge that is required to understand and treat human disease.

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth’s vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

INTRODUCTION: Diverse phenotypes, including large brains relative to body size, group living, and vocal learning ability, have evolved multiple times throughout mammalian history. These shared phenotypes may have arisen repeatedly by means of common mechanisms discernible through genome comparisons. RATIONALE: Protein-coding sequence differences have failed to fully explain the evolution of multiple mammalian phenotypes. This suggests that these phenotypes have evolved at least in part through changes in gene expression, meaning that their differences across species may be caused by differences in genome sequence at enhancer regions that control gene expression in specific tissues and cell types. Yet the enhancers involved in phenotype evolution are largely unknown. Sequence conservation–based approaches for identifying such enhancers are limited because enhancer activity can be conserved even when the individual nucleotides within the sequence are poorly conserved. This is due to an overwhelming number of cases where nucleotides turn over at a high rate, but a similar combination of transcription factor binding sites and other sequence features can be maintained across millions of years of evolution, allowing the function of the enhancer to be conserved in a particular cell type or tissue. Experimentally measuring the function of orthologous enhancers across dozens of species is currently infeasible, but new machine learning methods make it possible to make reliable sequence-based predictions of enhancer function across species in specific tissues and cell types. RESULTS: To overcome the limits of studying individual nucleotides, we developed the Tissue-Aware Conservation Inference Toolkit (TACIT). Rather than measuring the extent to which individual nucleotides are conserved across a region, TACIT uses machine learning to test whether the function of a given part of the genome is likely to be conserved. More specifically, convolutional neural networks learn the tissue- or cell type–specific regulatory code connecting genome sequence to enhancer activity using candidate enhancers identified from only a few species. This approach allows us to accurately associate differences between species in tissue or cell type–specific enhancer activity with genome sequence differences at enhancer orthologs. We then connect these predictions of enhancer function to phenotypes across hundreds of mammals in a way that accounts for species’ phylogenetic relatedness. We applied TACIT to identify candidate enhancers from motor cortex and parvalbumin neuron open chromatin data that are associated with brain size relative to body size, solitary living, and vocal learning across 222 mammals. Our results include the identification of multiple candidate enhancers associated with brain size relative to body size, several of which are located in linear or three-dimensional proximity to genes whose protein-coding mutations have been implicated in microcephaly or macrocephaly in humans. We also identified candidate enhancers associated with the evolution of solitary living near a gene implicated in separation anxiety and other enhancers associated with the evolution of vocal learning ability. We obtained distinct results for bulk motor cortex and parvalbumin neurons, demonstrating the value in applying TACIT to both bulk tissue and specific minority cell type populations. To facilitate future analyses of our results and applications of TACIT, we released predicted enhancer activity of >400,000 candidate enhancers in each of 222 mammals and their associations with the phenotypes we investigated. CONCLUSION: TACIT leverages predicted enhancer activity conservation rather than nucleotide-level conservation to connect genetic sequence differences between species to phenotypes across large numbers of mammals. TACIT can be applied to any phenotype with enhancer activity data available from at least a few species in a relevant tissue or cell type and a whole-genome alignment available across dozens of species with substantial phenotypic variation. Although we developed TACIT for transcriptional enhancers, it could also be applied to genomic regions involved in other components of gene regulation, such as promoters and splicing enhancers and silencers. As the number of sequenced genomes grows, machine learning approaches such as TACIT have the potential to help make sense of how conservation of, or changes in, subtle genome patterns can help explain phenotype evolution. [Image: see text] Tissue-Aware Conservation Inference Toolkit (TACIT) associates genetic differences between species with phenotypes. TACIT works by generating open chromatin data from a few species in a tissue related to a phenotype, using the sequences underlying open and closed chromatin regions to train a machine learning model for predicting tissue-specific open chromatin and associating open chromatin predictions across dozens of mammals with the phenotype. [Species silhouettes are from PhyloPic]

The precise pattern and timing of speciation events that gave rise to all living placental mammals remain controversial. We provide a comprehensive phylogenetic analysis of genetic variation across an alignment of 241 placental mammal genome assemblies, addressing prior concerns regarding limited genomic sampling across species. We compared neutral genome-wide phylogenomic signals using concatenation and coalescent-based approaches, interrogated phylogenetic variation across chromosomes, and analyzed extensive catalogs of structural variants. Interordinal relationships exhibit relatively low rates of phylogenomic conflict across diverse datasets and analytical methods. Conversely, X-chromosome versus autosome conflicts characterize multiple independent clades that radiated during the Cenozoic. Genomic time trees reveal an accumulation of cladogenic events before and immediately after the Cretaceous-Paleogene (K-Pg) boundary, implying important roles for Cretaceous continental vicariance and the K-Pg extinction in the placental radiation.

INTRODUCTION: Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits. RATIONALE: Sequencing advancements have identified millions of genetic changes between chimpanzee and human genomes; however, the functional impacts of the ~1 to 5% difference between our species is largely unknown. hCONDELs are one class of these predominantly noncoding sequence changes. Although large hCONDELs (>1 kb) have been previously identified, the vast majority of all hCONDELs (95.7%) are small (

Introduction: Use of antipsychotic drugs, especially second-generation agents, has been suggested to cause acute pancreatitis in multiple case reports; however, such an association has not been corroborated by larger studies. This study examined the association of antipsychotic drugs with risk of acute pancreatitis. Methods: Nationwide case–control study, based on data from several Swedish registers and including all 52,006 cases of acute pancreatitis diagnosed in Sweden between 2006 and 2019 (with up to 10 controls per case; n = 518,081). Conditional logistic regression models were used to calculate odds ratios (ORs) in current and past users of first-generation and second-generation antipsychotic drugs (dispensed prescription

Background Adjuvant postoperative treatment with aspirin and statins may improve survival in several solid tumors. This study aimed to assess whether these medications improve the survival after curatively intended treatment (including esophagectomy) for esophageal cancer in an unselected setting. Methods This nationwide cohort study included nearly all patients who underwent esophagectomy for esophageal cancer in Sweden from 2006 to 2015, with complete follow-up throughout 2019. Risk of 5-year disease-specific mortality in users compared to non-users of aspirin and statins was analyzed using Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI). The HRs were adjusted for age, sex, education, calendar year, comorbidity, aspirin/statin use (mutual adjustment), tumor histology, pathological tumor stage, and neoadjuvant chemo(radio)therapy. Results The cohort included 838 patients who survived at least 1 year after esophagectomy for esophageal cancer. Of these, 165 (19.7%) used aspirin and 187 (22.3%) used statins during the first postoperative year. Neither aspirin use (HR 0.92, 95% CI 0.67–1.28) nor statin use (HR 0.88, 95% CI 0.64–1.23) were associated with any statistically significant decreased 5-year disease-specific mortality. Analyses stratified by subgroups of age, sex, tumor stage, and tumor histology did not reveal any associations between aspirin or statin use and 5-year disease-specific mortality. Three years of preoperative use of aspirin (HR 1.26, 95% CI 0.98–1.65) or statins (HR 0.99, 95% CI 0.67–1.45) did not decrease the 5-year disease-specific mortality. Conclusions Use of aspirin or statins might not improve the 5-year survival in surgically treated esophageal cancer patients.

Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML posttreatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody–oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A- and TET2-mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts.Significance:This study offers a proof of principle of patient-personalized customized single-cell proteogenomics in AML including whole-genome sequencing–defined structural variants, currently unmeasurable by commercial “off-the-shelf” panels. This approach allows for the definition of genetic and immunophenotype features for an individual patient that would be best suited for measurable residual disease tracking.

Supplementary Data

Supplementary Methods

Figure S4

Table S1. Canine cohort metadata Table S2. Canine library preparation, amplification, and complexity Table S3. COSMIC Cancer Gene Census genes Table S4. Summary of canine RNA-seq data Table S5. RNA-seq validation Table S6. RNA-seq survey Table S7. Enrichment of protein domains in hemangiosarcoma and angiosarcoma Table S8. Canine somatic copy number aberrations by oaCGH Table S9. Comparison of top SCNAs in human Angiosarcoma Project data with canine oaCGH data Figure S1 - Canine exome sequencing workflow Figure S2 - Canine SMGs called in normal vs. overamplified libraries Figure S3 - Mutational landscape of entire canine cohort Figure S4 - Mutational landscape: FFPE vs Frozen Figure S5 - Mutational landscape: Canine Tumor Location Figure S6 - FFPE vs Frozen exome SCNA data clustering

Figure S7

Supplemental Table 7

Table S1. Demographic and pathological features of human patients with angiosarcoma Table S2. Demographic and pathological features of dogs with HSA Table S3. Primary antibodies for immunohistochemical evaluation Table S4. Gene ontology and biological functions of fusion partner genes in human angiosarcomas Table S5. Gene ontology and biological functions of fusion partner genes in canine HSAs Table S6. Detection of fusion genes in canine HSAs by RT-PCR Table S7. Biological functions associated with 490 upregulated genes in human angiosarcomas Table S8. Association of frequency between fusion genes, TP53 and PIK3CA mutations Table S9. Association of fusion genes with dog signalment and tumor histology Table S10. Association of frequency between fusion genes, TP53 and PIK3CA mutations Table S11. 41 differentially expressed genes in PF (n = 4) compared to P (n = 9) group Table S12. 212 differentially expressed genes in PF (n = 4) compared to PK (n = 6) group Table S13. 377 differentially expressed genes in PF (n = 4) compared to PFK (n = 4) group Table S14. Immunohistochemical features of human angiosarcomas Table S15. Immunohistochemical features of canine HSAs

Supplementary Data

PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti–PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53−/− HCCs led to T cell–mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53−/− HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin–driven tumors were resistant to anti–PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti–PD-1 and could represent a novel biomarker for HCC patient exclusion.Significance:Determinants of response to anti–PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti–PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion.See related commentary by Berraondo et al., p. 1003.This article is highlighted in the In This Issue feature, p. 983

Angiosarcoma is a highly aggressive cancer of blood vessel–forming cells with few effective treatment options and high patient mortality. It is both rare and heterogenous, making large, well-powered genomic studies nearly impossible. Dogs commonly suffer from a similar cancer, called hemangiosarcoma, with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. If the clinical similarity of canine hemangiosarcoma and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine hemangiosarcoma via whole-exome sequencing (47 golden retriever hemangiosarcomas) and RNA sequencing (74 hemangiosarcomas from multiple breeds). Somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). The predominant mutational signature was the age-associated deamination of cytosine to thymine. As reported in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. We compared the canine data to human data recently released by The Angiosarcoma Project, and found many of the same genes and pathways significantly enriched for somatic mutations, particularly in breast and visceral angiosarcomas. Canine hemangiosarcoma closely models the genomic landscape of human angiosarcoma of the breast and viscera, and is a powerful tool for investigating the pathogenesis of this devastating disease.Implications:We characterize the genomic landscape of canine hemangiosarcoma and demonstrate its similarity to human angiosarcoma.

Detailed Methods for Immunohistochemistry Detailed Description of the Canine Clinical Study eBAT Pharmacokinetics and Neutralizing Antibody Assays Supplementary Table 1. Correlation between patient covariates and death Supplementary Table 2: Patient information (TMA) Supplementary Table 3: Cox regression analysis for time-to-progression Supplementary Figure 1. Survival probability based on EGFR Supplementary Figure 2. Quantification of EGFR and uPAR expression in normal canine tissues and in canine hemangiosarcoma Supplementary Figure 3. CONSORT diagram for SRCBST study