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Background Advancements in treatment and supportive care have led to improved survival for adolescents and young adults (AYAs) with cancer; however, a subset of those diagnosed remain at risk for early death (within 2 months of diagnosis). Factors that place AYAs at increased risk of early death have not been well studied. Methods The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death in AYAs with hematologic malignancies, central nervous system tumors, and solid tumors. Associations between age at diagnosis, sex, race, ethnicity, socioeconomic status, insurance status, rurality, and early death were assessed. Results A total of 268 501 AYAs diagnosed between 2000 and 2016 were included. Early death percentage was highest in patients diagnosed with hematologic malignancies (3.1%, 95% confidence interval [CI] = 2.9% to 3.2%), followed by central nervous system tumors (2.5%, 95% CI = 2.3% to 2.8%), and solid tumors (1.0%, 95% CI = 0.9% to 1.0%). Age at diagnosis, race, ethnicity, lower socioeconomic status, and insurance status were associated with increased risk of early death in each of the cancer types. For AYAs with hematologic malignancies and solid tumors, risk of early death decreased statistically significantly over time. Conclusions A subset of AYAs with cancer remains at risk for early death. In addition to cancer type, sociodemographic factors also affect risk of early death. A better understanding of the interplay of factors related to cancer type, treatment, and health systems that place certain AYA subsets at higher risk for early death is needed to address these disparities and improve outcomes.

BACKGROUND: Exposure to workplace violence is associated with physical and/or psychological trauma. Despite its significant impact, little is known about front-line workers’ experiences of preventing workplace violence. OBJECTIVE: This study aimed to identify what workers identify as important to preventing workplace conflicts from escalating into violence. METHODS: We conducted seventeen qualitative focus-group interviews with fifty-eight workers at the Danish Prison and Probation Service and psychiatric hospitals. We applied thematic analysis to identify types of violence-prevention practices, and prerequisites for successfully preventing workplace violence. RESULTS: We identified two main categories of violence-prevention practices, and one main category of prerequisites for violence-prevention practices. Main category A), “the individual worker’s violence-prevention practices” included the sub-categories, 1) identify the causes of workplace violence and potentially violent situations, 2) establish relationships, state rules, and set clear boundaries and 3) display empathy and communicate respectfully. Main category B), “collaborative practices for preventing workplace violence” included 4) communicate with co-workers, and share information and observations, 5) coordinate work, avoid being played off against colleagues, and support colleagues. Main category C), “prerequisites for violence-prevention practices” included 6) managing one’s emotions, and 7) having sufficient time to do the job, and being a part of a stable team, whose members know each other and the inmates/patients”. CONCLUSION: This study contributes to a better understanding of the interplay among individual, collaborative, and contextual aspects of preventing workplace violence. We believe that an increased understanding of the complexity of preventing workplace violence in high-risk sectors is useful when designing comprehensive violence-prevention strategies.

Understanding the composition and activation of multicomponent receptor complexes is a challenge in biology. To address this, we developed a synthetic approach based on nanobodies to drive assembly and activation of cell surface receptors and apply the concept by manipulating receptors that govern plant symbiosis with nitrogen-fixing bacteria. We show that the Lotus japonicus Nod factor receptors NFR1 and NFR5 constitute the core receptor complex initiating the cortical root nodule organogenesis program as well as the epidermal program controlling infection. We find that organogenesis signaling is mediated by the intracellular kinase domains whereas infection requires functional ectodomains. Finally, we identify evolutionarily distant barley receptors that activate root nodule organogenesis, which could enable engineering of biological nitrogen-fixation into cereals.

Vascular inflammation can be detected in the pericoronary adipose tissue (PCAT) by coronary computed tomography angiography (CCTA) attenuation. Treatment with liraglutide is associated with anti-inflammatory effects and reduces cardiovascular risk in diabetic patients. This study is aimed at examining the effect of clinically indicated liraglutide on PCAT attenuation. Asymptomatic patients with type 2 diabetes mellitus (T2DM) and without known ischemic heart disease underwent clinical examination, blood analysis, and CCTA. The main coronary arteries were outlined and PCAT attenuation was measured on the proximal 40 mm. Patients treated with liraglutide on a clinical indication were compared to patients not receiving liraglutide. The study included 190 patients; 53 (28%) received liraglutide (Lira+) and 137 (72%) did not (Lira-). There were no significant differences in PCAT attenuation between the two groups in either artery. However, PCAT attenuation measured around the left anterior descending artery (LAD) was lower in the Lira+ group after adjustment for age, sex, body mass index, and T2DM duration ( b coefficient -2.4, p = 0.029 ). In a population of cardiac asymptomatic T2DM patients, treatment with clinically indicated liraglutide was not associated with differences in PCAT attenuation compared to nonliraglutide treatment in the unadjusted model. An association was seen in the adjusted model for the left anterior descending artery, possibly indicating an anti-inflammatory effect.

BACKGROUND: Associations between degrees of postoperative hyperglycemia and morbidity has previously been established. There may be an association between the glycemic profile and patient-reported recovery, and this may be a target for perioperative quality improvements. We aimed to investigate the association between metrics of the 30-day glycemic profile and patient-reported recovery in non-diabetic patients after major abdominal surgery.METHODS: In a prospective, explorative cohort study, non-diabetic adult patients undergoing acute, major abdominal surgery were included within 24 hours after surgery. Interstitial fluid glucose concentration was measured for 30 consecutive days with a continuous glucose measurement device. The validated questionnaire 'Quality of Recovery-15' was used to assess patient-reported quality of recovery on postoperative days 10, 20, and 30. Follow-up time was divided into five-day postoperative intervals using days 26-30 as a reference. Linear mixed models were applied to investigate temporal changes in mean p-glucose, coefficient of variation, time within 70-140mg/dL, and time above 200mg/dL in relation to patient-reported recovery.RESULTS: Twenty-seven patients completed the study per protocol. A hyperglycemic event (>200 mg/dL) occurred in 18 of 27 patients (67%) within the first three postoperative days. Compared to the reference period, the coefficient of variation was significantly increased during all time intervals, indicating prolonged postoperative insulin resistance. During 30 days of follow-up, patient-reported recovery was associated with the coefficient of variation measured for three and five days before the corresponding recovery score assessment (recovery score estimate -1.52 [pCONCLUSION: Alterations in the glycemic profile are frequent and prolonged during the first postoperative month after major surgery probably due to peripheral insulin resistance. Our findings indicate that high glycemic variation is associated with poorer patient-reported recovery and might represent a proxy for care improvements in the postoperative period. This article is protected by copyright. All rights reserved.

There is a growing population of adolescent and young adult (AYA, ages 15-39 at diagnosis) cancer survivors at heightened risk of chronic conditions. Moderate to vigorous physical activity level (MVPA) is an important modifiable factor associated with improved cardiovascular health. Little is known about the association of sociodemographic factors with MVPA in AYA survivors.Self-reported data from the National Health Interview Survey (2009-2018) were used to identify AYA cancer survivors (at least 2 years post-diagnosis) and age- and sex-matched controls. MVPA level based on sociodemographic (sex, race and ethnicity, income, education), medical (heart disease, stroke, and diabetes), and cardiovascular risk factors (BMI and smoking) was determined within and between survivors and controls using multivariable linear regression models.A total of 4766 AYA cancer survivors and 47,660 controls were included. Less than half of survivors (41.9%) and controls (43.2%) met MVPA guideline recommendations, and one-third of survivors (33.4%) reported no MVPA. Black race was associated with reduced MVPA compared with White race (ratio: 0.58 (95% CI: 0.37-0.90). Household income $50,000/year, education high school, diagnoses of diabetes or heart disease, and current smoking were all significantly associated with reduced MVPA in AYA survivors. There were no differences in MVPA between survivors and controls by sociodemographic factors, medical history, and cardiovascular risk factors.We found disparities in MVPA in AYA cancer survivors by sociodemographic, medical, and cardiovascular risk factors. Understanding trajectories of MVPA among different sociodemographic populations is needed to identify opportunities for intervention.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy that may lead to organ failure. Dysregulation of the complement system can cause aHUS, and various disease-related variants in the complement regulatory protein CD46 are described. We here report a pediatric patient with aHUS carrying a hitherto unreported homozygous variant in CD46 (NM_172359.3:c.602C>T p.(Ser201Leu)). In our functional analyses, this variant caused complement dysregulation through three separate mechanisms. First, CD46 surface expression on the patient's blood cells was significantly reduced. Second, stably expressing CD46(Ser201Leu) cells bound markedly less to patterns of C3b than CD46 WT cells. Third, the patient predominantly expressed the rare isoforms of CD46 (C dominated) instead of the more common isoforms (BC dominated). Using BC1 and C1 expressing cell lines, we found that the C1 isoform bound markedly less C3b than the BC1 isoform. These results highlight the coexistence of multiple mechanisms that may act synergistically to disrupt CD46 function during aHUS development.

The Coronavirus Disease 2019 (COVID-19) pandemic has been accompanied by increased prenatal maternal distress (PMD). PMD is associated with adverse pregnancy outcomes which may be mediated by the placenta. However, the potential impact of the pandemic on in vivo placental development remains unknown. To examine the impact of the pandemic and PMD on in vivo structural placental development using advanced magnetic resonance imaging (MRI), acquired anatomic images of the placenta from 63 pregnant women without known COVID-19 exposure during the pandemic and 165 pre-pandemic controls. Measures of placental morphometry and texture were extracted. PMD was determined from validated questionnaires. Generalized estimating equations were utilized to compare differences in PMD placental features between COVID-era and pre-pandemic cohorts. Maternal stress and depression scores were significantly higher in the pandemic cohort. Placental volume, thickness, gray level kurtosis, skewness and run length non-uniformity were increased in the pandemic cohort, while placental elongation, mean gray level and long run emphasis were decreased. PMD was a mediator of the association between pandemic status and placental features. Altered in vivo placental structure during the pandemic suggests an underappreciated link between disturbances in maternal environment and perturbed placental development. The long-term impact on offspring is currently under investigation.

Background: There is a growing population of adolescent and young adult (AYA, age 15–39 years) acute leukemia survivors in whom long-term mortality outcomes are largely unknown. Methods: The current study utilized the Surveillance, Epidemiology, and End Results (SEER) registry to assess long-term outcomes of AYA acute leukemia 5-year survivors. The impact of diagnosis age, sex, race/ethnicity, socioeconomic status, and decade of diagnosis on long-term survival were assessed utilizing an accelerated failure time model. Results: A total of 1,938 AYA acute lymphoblastic leukemia (ALL) and 2,350 AYA acute myeloid leukemia (AML) survivors diagnosed between 1980 and 2009 were included with a median follow-up of 12.3 and 12.7 years, respectively. Ten-year survival for ALL and AML survivors was 87% and 89%, respectively, and 99% for the general population. Survival for AYA leukemia survivors remained below that of the age-adjusted general population at up to 30 years of follow-up. Primary cancer mortality was the most common cause of death in early survivorship with noncancer causes of death becoming more prevalent in later decades of follow-up. Male AML survivors had significantly worse survival than females (survival time ratio: 0.61, 95% confidence interval: 0.45–0.82). Conclusions: AYA leukemia survivors have higher mortality rates than the general population that persist for decades after diagnosis. Impact: While there have been improvements in late mortality, long-term survival for AYA leukemia survivors remains below that of the general population. Studies investigating risk factors for mortality and disparities in late effects among long-term AYA leukemia survivors are needed.

Supplementary Figures S1-8. Figure S1 - Analysis of nonlinear blending synergy for the pairs of antibodies that constitute Pan-HER. Figure S2 - In vitro comparison of Pan-HER and a combination of cetuximab, trastuzumab and MM-121. Figure S3 - In vivo assessment of nonlinear blending synergy for the target specificities in the Pan-HER mixture. Figure S4 - Dose titration of Pan-HER in the BxPC3 xenograft model. Figure S5 - IHC analysis of Calu-3 tumors. Figure S6 - Assessment of cell death and cell cycle arrest. Figure S7 - Assessment of ADCC in a panel of cell lines. Figure S8 - Analysis of the effect of receptor internalization on effector functions.

Supplementary Methods. Description of methods used for assessment of synergy, immunohistochemistry, cell death, cell cycle arrest, ADCC and CDC.

Supplementary Tables S1-2. Table S1 - Source, origin, subtype and growth medium for each cell line. Table S2 - Characteristics of tested patient-derived xenograft models.

Purpose: Accumulating evidence indicates a high degree of plasticity and compensatory signaling within the human epidermal growth factor receptor (HER) family, leading to resistance upon therapeutic intervention with HER family members.Experimental Design/Results: We have generated Pan-HER, a mixture of six antibodies targeting each of the HER family members EGFR, HER2, and HER3 with synergistic pairs of antibodies, which simultaneously remove all three targets, thereby preventing compensatory tumor promoting mechanisms within the HER family. Pan-HER induces potent growth inhibition in a range of cancer cell lines and xenograft models, including cell lines with acquired resistance to therapeutic antibodies. Pan-HER is also highly efficacious in the presence of HER family ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. All three target specificities contribute to the enhanced efficacy, demonstrating a distinct benefit of combined HER family targeting when compared with single-receptor targeting.Conclusions: Our data show that simultaneous targeting of three receptors provides broader efficacy than targeting a single receptor or any combination of two receptors in the HER family, especially in the presence of HER family ligands. Pan-HER represents a novel strategy to deal with primary and acquired resistance due to tumor heterogeneity and plasticity in terms of HER family dependency and as such may be a viable alternative in the clinic. Clin Cancer Res; 21(18); 4110–22. ©2015 AACR.See related commentary by Yarden and Sela, p. 4030

Non-indigenous species (NIS) are of concern for biodiversity conservation and ecosystem functioning. We present an updated list of NIS, including cryptogenic species, from Danish marine waters containing 123 species. Benthic invertebrates (36%) and phytoplankton (28%) dominate the list, but fish (15%) and macroalgae (13%) are also important. The Limfjord in Northern Jutland emerges as a hotspot for the introduction of NIS. Data from multiple sources were included, i.e., the National Monitoring Program (NOVANA), the National Fish Atlas project, the citizen science project Arter.dk, research articles, and annual national reports of the ICES working group ITMO. Forty-six NIS species were subject to expert judging using a modified Harmonia protocol; 19 were found to fulfil the four selected criteria identifying a species as being ‘invasive’. Additionally, 38 species, not yet recorded in Danish waters, were evaluated using the same method, and 31 were found to fulfil the ‘invasive’ criteria. For nine selected species, introduction history, distribution maps, and time-series diagrams are presented. Our data document that the national monitoring efforts should be expanded to record macrozooplankton, coastal fish, and mobile epibenthic species. Furthermore, the national data repository, Arter.dk, should be expanded to enable more detailed documentation of new NIS records.

We present all-order predictions for Higgs boson production plus at least one jet which are accurate to leading logarithm in $\hat s/|p_\perp|^2$. Our calculation includes full top and bottom quark mass dependence at all orders in the logarithmic part, and to highest available order in the tree-level matching. The calculation is implemented in the framework of High Energy Jets (HEJ). This is the first cross section calculated with $\log(\hat s)$ resummation and matched to fixed order for a process requiring just one jet, and our results also extend the region of resummation for processes with two jets or more. This is possible because the resummation is performed explicitly in phase space. We compare the results of our new calculation to LHC data and to next-to-leading order predictions and find a numerically significant impact of the logarithmic corrections in the shape of key distributions, which remains after normalisation of the cross section., 21 pages, 11 figures; v2: plots updated with HX component, matches published version

We recently reported that an interdisciplinary multicomponent goals-of-care (myGOC) program was associated with an improvement in goals-of-care (GOC) documentation and hospital outcomes; however, it is unclear if the benefit was uniform between patients with hematologic malignancies and solid tumors. In this retrospective cohort study, we compared the change in hospital outcomes and GOC documentation before and after myGOC program implementation between patients with hematologic malignancies and solid tumors. We examined the change in outcomes in consecutive medical inpatients before (May 2019–December 2019) and after (May 2020–December 2020) implementation of the myGOC program. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included GOC documentation. In total, 5036 (43.4%) patients with hematologic malignancies and 6563 (56.6%) with solid tumors were included. Patients with hematologic malignancies had no significant change in ICU mortality between 2019 and 2020 (26.4% vs. 28.3%), while patients with solid tumors had a significant reduction (32.6% vs. 18.8%) with a significant between-group difference (OR 2.29, 95% CI 1.35, 3.88; p = 0.004). GOC documentation improved significantly in both groups, with greater changes observed in the hematologic group. Despite greater GOC documentation in the hematologic group, ICU mortality only improved in patients with solid tumors.

Immunoglobulin E is a mammal specific antibody isotype supporting the immune response against parasites and venoms, but also a driver of allergic responses. Structural and biophysical studies have defined the conformation of the IgE Fc fragment bound to the cell surface receptor FcεRIα and the dynamic properties of the IgE Fc. How these prior studies translate to the full antibody-receptor complex remains unknown. Here we show that IgE bound to the FcεRIα adopts two distinct defined conformations. In a cryo-EM structure of the IgE FcεRIα complex, IgE adopts a T-like conformation where the antigen binding Fab arms may be parallel to the cell membrane. A second Y-like conformation captured in negative stain EM features a different arrangement with two Fab arms likely to orient away from the membrane. Solution studies suggest the two receptor bound IgE conformations to be present in a 2:1 ratio. Introduction of flexibility in the Fab-Fc hinge diminishes the biological activity of IgE demonstrating a functional role for the observed defined Fab-Fc hinge conformations.

Streams of event weights in particle-level Monte Carlo event generators are a convenient and immensely CPU-efficient approach to express systematic uncertainties in phenomenology calculations, providing systematic variations on the nominal prediction within a single event sample. But the lack of a common standard for labelling these variation streams across different tools has proven to be a major limitation for event-processing tools and analysers alike. Here we propose a well-defined, extensible community standard for the naming, ordering, and interpretation of weight streams that will serve as the basis for semantically correct parsing and combination of such variations in both theoretical and experimental studies., 11 pages

Introduction: Patients with chronic intestinal failure (IF) have a low degree of physical activity, decreased muscle mass, and decreased muscle strength, leading to a high risk of sarcopenia. We aimed to test the prevalence of sarcopenia by the use of SARC-F and EWGSOP and to investigate the association between the two at baseline and after 12 weeks of an exercise intervention.Methods: Thirty-one patients with chronic IF completed 12 weeks of three weekly home-based individualized exercise sessions. Body composition was measured by bioimpedance analysis and physical function by handgrip strength (HGS) and timed up-and-go (TUG). Sarcopenia was assessed by SARC-F and EWGSOP. Multiple regression analysis was used to test for the association between the two tools. Results: The prevalence of sarcopenia measured by EWGSOP was 59%. This prevalence did not change after the intervention. At baseline, 38.8% of patients were screened as at risk for sarcopenia by SARC-F. This decreased to 29.0% after the intervention (P < 0.001). A statistically significant increase was achieved in muscle mass (P = 0.017) and muscle mass index (P = 0.016). Furthermore, both TUG (P = 0.033) and HGS (P = 0.019) improved. Conclusions: Sarcopenia is prevalent in patients with chronic IF. EWGSOP finds more patients to be at risk of sarcopenia than SARC-F but was not sufficiently sensitive to measure changes induced by the physical intervention. The significant change in SARC-F may illustrate that patients, themselves, find an improvement in self-perceived health.

BACKGROUND: Peripheral nerve blocks (PNB) have recently been recommended in total hip (THA) and knee (TKA) arthroplasty as they may reduce pain, morphine consumption, length of stay (LOS) and complications. However, whether PNBs are associated with early discharge within an enhanced recovery protocol including multimodal analgesia is uncertain.METHODS: An observational multicenter study from January to August 2017 in six Danish Arthroplasty Centers with established fast-track protocols. Prospective recording of preoperative characteristics and information on PNB, LOS and readmissions through the Danish National Patient Registry and medical records. Multiple logistic regression was used to investigate associations between PNB and a LOS >1 day, LOS >4 days, and 30-days readmissions. We also reported on mobilization, pain, opioid and fall-related complications leading to LOS >4 days or readmissions.RESULTS: A total of 2027 (58.6%) THA and 1432 (41.4%) TKAs with a median LOS of 1 day (IQR 1-2) and 5.3% (CI:4.6-6.1) 30-days readmission rate were identified. PNB was used in 40.7% (CI:38.2-43.3) of TKA and 2.7% (CI:2.0-3.5) of THA, but with considerable interdepartmental variation (0.0-89.0% for TKA). There was no association between PNB and LOS >1 day (OR:1.19 CI:0.82-1.72; p = .354), LOS >4 days (OR:1.4 CI:0.68-2.89; p = .359) or 30-days readmissions (OR:1.02 CI:0.63-1.65; p = .935) in TKA. Logistic regression in THA was not possible due to limited use of PNB. In TKA there were 12 (2.1% CI:1.2-3.6) with and 1 (0.1% CI:0.02-0.7) without a PNB, who had mobilization, pain or opioid-related complications, and 5 (0.9% CI:0.4-2.0) versus 4 (0.5% CI:0.2-1.2) who fell. Correspondingly, 2 (3.7% CI:1.0-12.6) and 11 (0.6% CI:0.3-1.0) of THA patients had these complications, while 0 (0.0% CI:0.0-6.6) and 17 (0.8% CI:0.5-1.3) fell.CONCLUSION: Routine use of peripheral nerve blocks was not associated with early discharge or 30-days readmissions in fast-track THA and TKA. Future studies should focus on benefits of PNB in high-risk patients.

IntroductionAcute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities.MethodsA scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention.Results205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease.ConclusionsAP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.

The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact wholebody glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.

ObjectivesTo investigate the predictive performance of the Fetal Medicine Foundation (FMF) first-trimester screening algorithm for pre-eclampsia in a Danish population and compare screening performance with that of the current Danish strategy, which is based on maternal risk factors.MethodsThis was a prospective study of women with a singleton pregnancy attending for their first-trimester ultrasound scan and screening for aneuploidies at six Danish university hospitals between May 2019 and December 2020. Prenatal data on maternal characteristics and medical history were recorded, and measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum pregnancy-associated plasma protein-A (PAPP-A) and serum placental growth factor (PlGF) were collected without performing a risk assessment for pre-eclampsia. Information on acetylsalicylic acid use was recorded. After delivery, pregnancy outcome, including gestational age at delivery and pre-eclampsia diagnosis, was recorded. Pre-eclampsia risk assessment for each woman was calculated blinded to outcome using the FMF screening algorithm following adjustment to the Danish population. Detection rates (DRs) of the FMF algorithm were calculated for a fixed screen-positive rate (SPR) of 10% and for the SPR achieved in the current Danish screening.ResultsA total of 8783 pregnant women were included, with a median age of 30.8 (interquartile range (IQR), 28.1–33.9) years. The majority were white (95%), naturally conceiving (90%), non-smokers (97%) and had no family history of pre-eclampsia (96%). The median body mass index was 23.4 (IQR, 21.2–26.6) kg/m2. A complete risk assessment including maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A was available for 8156 women (92.9%). In these women, UtA-PI was measured bilaterally with a median value of 1.58 (IQR, 1.27–1.94) and the median resting MAP of 80.5 (IQR, 76.1–85.4) mmHg in two consecutive measurements. Among these, 303 (3.7%) developed pre-eclampsia, including 55 (0.7%) cases of pre-eclampsia with delivery ConclusionIn this large Danish multicenter study, the FMF algorithm based on maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A predicted 77.4% of cases with pre-eclampsia with delivery Objectives: To investigate the predictive performance of the Fetal Medicine Foundation (FMF) first-trimester screening algorithm for pre-eclampsia in a Danish population and compare screening performance with that of the current Danish strategy, which is based on maternal risk factors. Methods: This was a prospective study of women with a singleton pregnancy attending for their first-trimester ultrasound scan and screening for aneuploidies at six Danish university hospitals between May 2019 and December 2020. Prenatal data on maternal characteristics and medical history were recorded, and measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum pregnancy-associated plasma protein-A (PAPP-A) and serum placental growth factor (PlGF) were collected without performing a risk assessment for pre-eclampsia. Information on acetylsalicylic acid use was recorded. After delivery, pregnancy outcome, including gestational age at delivery and pre-eclampsia diagnosis, was recorded. Pre-eclampsia risk assessment for each woman was calculated blinded to outcome using the FMF screening algorithm following adjustment to the Danish population. Detection rates (DRs) of the FMF algorithm were calculated for a fixed screen-positive rate (SPR) of 10% and for the SPR achieved in the current Danish screening. Results: A total of 8783 pregnant women were included, with a median age of 30.8 (interquartile range (IQR), 28.1–33.9) years. The majority were white (95%), naturally conceiving (90%), non-smokers (97%) and had no family history of pre-eclampsia (96%). The median body mass index was 23.4 (IQR, 21.2–26.6) kg/m2. A complete risk assessment including maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A was available for 8156 women (92.9%). In these women, UtA-PI was measured bilaterally with a median value of 1.58 (IQR, 1.27–1.94) and the median resting MAP of 80.5 (IQR, 76.1–85.4) mmHg in two consecutive measurements. Among these, 303 (3.7%) developed pre-eclampsia, including 55 (0.7%) cases of pre-eclampsia with delivery < 37 weeks of gestation and 16 (0.2%) cases of pre-eclampsia with delivery < 34 weeks. At a SPR of 10%, combined screening using the FMF algorithm based on maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A had a DR of 77.4% (95% CI, 57.6–97.2%) for pre-eclampsia with delivery < 34 weeks, 66.8% (95% CI, 54.4–79.1%) for pre-eclampsia with delivery < 37 weeks and 44.1% (95% CI, 38.5–49.7%) for pre-eclampsia with delivery at any gestational age. The current Danish screening strategy using maternal risk factors detected 25.0% of women with pre-eclampsia with delivery < 34 weeks and 19.6% of women with pre-eclampsia with delivery < 37 weeks at a SPR of 3.4%. When applying the FMF algorithm including maternal characteristics, MAP, UtA-PI and PlGF at the fixed SPR of 3.4%, the DRs were 60.5% (95% CI, 36.9–84.1%) for PE with delivery < 34 weeks and 45.2% (95% CI, 32.0–58.5%) for PE with delivery < 37 weeks. Conclusion: In this large Danish multicenter study, the FMF algorithm based on maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A predicted 77.4% of cases with pre-eclampsia with delivery < 34 weeks and 66.8% of cases with pre-eclampsia with delivery < 37 weeks of gestation at a SPR of 10%, suggesting that the performance of the algorithm in a Danish cohort matches that in other populations.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body’s first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin’s anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.

Receptors that distinguish the multitude of microbes surrounding plants in the environment enable dynamic responses to the biotic and abiotic conditions encountered. In this study, we identify and characterise a glycan receptor kinase, EPR3a, closely related to the exopolysaccharide receptor EPR3. Epr3a is up-regulated in roots colonised by arbuscular mycorrhizal (AM) fungi and is able to bind glucans with a branching pattern characteristic of surface-exposed fungal glucans. Expression studies with cellular resolution show localised activation of the Epr3a promoter in cortical root cells containing arbuscules. Fungal infection and intracellular arbuscule formation are reduced in epr3a mutants. In vitro, the EPR3a ectodomain binds cell wall glucans in affinity gel electrophoresis assays. In microscale thermophoresis (MST) assays, rhizobial exopolysaccharide binding is detected with affinities comparable to those observed for EPR3, and both EPR3a and EPR3 bind a well-defined β-1,3/β-1,6 decasaccharide derived from exopolysaccharides of endophytic and pathogenic fungi. Both EPR3a and EPR3 function in the intracellular accommodation of microbes. However, contrasting expression patterns and divergent ligand affinities result in distinct functions in AM colonisation and rhizobial infection in Lotus japonicus. The presence of Epr3a and Epr3 genes in both eudicot and monocot plant genomes suggest a conserved function of these receptor kinases in glycan perception.

The aim of this study was to determine in utero fetal-placental growth patterns using in vivo three-dimensional (3D) quantitative magnetic resonance imaging (qMRI).Healthy women with singleton pregnancies underwent fetal MRI to measure fetal body, placenta, and amniotic space volumes. The fetal-placental ratio (FPR) was derived using 3D fetal body and placental volumes (PV). Descriptive statistics were used to describe the association of each measurement with increasing gestational age (GA) at MRI.Fifty-eight (58) women underwent fetal MRI between 16 and 38 completed weeks gestation (mean = 28.12 ± 6.33). PV and FPR varied linearly with GA at MRI (rWe describe in-utero growth trajectories of fetal-placental volumes in healthy pregnancies using qMRI. Understanding healthy in utero development can establish normative benchmarks where departures from normal may identify early in utero placental failure prior to the onset of fetal harm.

Pleuroscopy with pleural biopsy has a high sensitivity for malignant pleural effusion (MPE). Because MPEs tend to recur, concurrent diagnosis and treatment of MPE during pleuroscopy is desired. However, proceeding directly to treatment at the time of pleuroscopy requires confidence in the on-site diagnosis. The study's primary objective was to create a predictive model to estimate the probability of MPE during pleuroscopy.A prospective observational multicentre cohort study of consecutive patients undergoing pleuroscopy was conducted. We used a logistic regression model to evaluate the probability of MPE with relation to visual assessment, rapid on-site evaluation (ROSE) of touch preparation and presence of pleural nodules/masses on computed tomography (CT). To assess the model's prediction accuracy, a bootstrapped training/testing approach was utilized to estimate the cross-validated area under the receiver operating characteristic curve.Of the 201 patients included in the study, 103 had MPE. Logistic regression showed that higher level of malignancy on visual assessment is associated with higher odds of MPE (OR = 34.68, 95% CI = 9.17-131.14, p 0.001). The logistic regression also showed that higher level of malignancy on ROSE of touch preparation is associated with higher odds of MPE (OR = 11.63, 95% CI = 3.85-35.16, p 0.001). Presence of pleural nodules/masses on CT is associated with higher odds of MPE (OR = 6.61, 95% CI = 1.97-22.1, p = 0.002). A multivariable logistic regression model of final pathologic status with relation to visual assessment, ROSE of touch preparation and presence of pleural nodules/masses on CT had a cross-validated AUC of 0.94 (95% CI = 0.91-0.97).A prediction model using visual assessment, ROSE of touch preparation and CT scan findings demonstrated excellent predictive accuracy for MPE. Further validation studies are needed to confirm our findings.

Background Compared with their ensured counterparts, uninsured adolescents and young adults (AYAs) with cancer are more likely to present with advanced disease and have poor prognoses. The Patient Protection and Affordable Care Act (ACA), enacted in 2010, provided health care coverage to millions of uninsured young adults by allowing them to remain on their parents’ insurance until age 26 years (the Dependent Care Expansion, DCE). The impact of the expansion of insurance coverage on survival outcomes for young adults with cancer has not been assessed. Participants Utilizing the Surveillance, Epidemiology, and End Results database, we identified all patients aged 12-16 (younger-AYAs), 19-23 (middle-AYAs), and 26-30 (older-AYAs) who were diagnosed with cancer between 2006-2008 (pre-ACA) and 2011-2013 (post-ACA). Methods In this population-based cohort study, we used an accelerated failure time model to assess changes in survival rates before and after the enactment of the ACA DCE. Results Middle-AYAs ages 19-23 (thus eligible to remain on their parents’ insurance) experienced significantly increased 2-year survival after the enactment of the ACA DCE (survival time ratio 1.25, 95% confidence interval: 0.75-2.43, P = .029) and that did not occur in younger-AYAs (ages 12-16). Patients with sarcoma and acute myeloid leukemia accounted for the majority of improvement in survival. Middle-AYAs of hispanic ethnicity and those with low socioeconomic status experienced trends of improved survival after the ACA DCE was enacted. Conclusion Survival outcomes improved for young adults with cancer following the expansion of health insurance coverage. Efforts are needed to expand coverage for the millions of young adults who do not have health insurance.

To assess whether a quality improvement bundle focusing on prevention is effective in reducing pressure injury (PI) incidence or costs or delaying PI onset.A combined retrospective/prospective cohort study was performed at an academic tertiary care ICU on all patients admitted with a length of stay longer than 48 hours and Braden scale score of 18 or less. Following retrospective data collection (preintervention), a multimodal quality improvement bundle focusing on PI prevention through leadership initiatives, visual tools, and staff/patient education was developed, and data were prospectively collected (postintervention).Statistical and cost analyses were performed comparing both cohorts. A total of 930 patients met the study inclusion criteria (preintervention, n = 599; postintervention, n = 331). A significant decrease in PI incidence was observed from preintervention (n = 37 [6%]) to postintervention (n = 7 [2%], P = .005). This led to a predicted yearly cost savings of $826,810. Further, a significant increase in time to PI occurrence was observed from preintervention (mean, 5 days) to postintervention (mean, 9 days; P = .04). Staff were compliant with the bundle implementation 80% of the time.Implementation of the quality improvement bundle focused on multimodal PI prevention in critically ill patients led to a significant reduction in PI incidence, increased time to PI occurrence, and was cost-effective.

Peatlands are a significant global carbon (C) store, which can be compromised by drainage and afforestation. Quantifying the rate of C loss from peat soils under forestry is challenging, as soil CO2 efflux includes both CO2 produced from heterotrophic peat decomposition and CO2 produced by tree roots and associated fungal networks (autotrophic respiration). We experimentally terminated autotrophic below-ground respiration in replicated forest plots by cutting through all living tree roots (trenching) and measured soil surface CO2 flux, litter input, litter decay rate, and soil temperature and moisture over 2 years. Decomposition of cut roots was measured and CO2 fluxes were corrected for this, which resulted in a large change in the fraction heterotrophic : autotrophic flux, suggesting that even 2 years after trenching decaying root biomass makes significant contributions to the CO2 flux. Annual peat decomposition (heterotrophic CO2 flux) was 115 ± 16 g C m−2 yr−1, representing ca. 40 % of total soil respiration. Decomposition of needle litter is accelerated in the presence of an active rhizosphere, indicating a priming effect by labile C inputs from roots. This suggests that our estimates of peat mineralization in our trenched plots are conservative and underestimate overall rates of peat C loss. Considering also input of litter from trees, our results indicate that the soils in these 30-year-old drained and afforested peatlands are a net sink for C, since substantially more C enters the soil organic matter than is decomposed heterotrophically. This study does not account for fluvial C fluxes, which represent a small flux compared to the CO2 soil efflux; further, root litter and exudate deposition could be a significant C source that is only partially sampled by our approach, adding to these plantations being a potential carbon sink. However, the C balance for these soils should be taken over the lifespan of the trees, in order to determine if the soils under these drained and afforested peatlands are a sustained sink of C or become a net source over longer periods of forestry.

With the increased demand for controlled deterministic growth of III–V semiconductors at the nanoscale, the impact and interest of understanding defect formation and crystal structure switching becomes increasingly important. Vapor–liquid–solid (VLS) growth of semiconductor nanocrystals is an important mechanism for controlling and studying the formation of individual crystal layers and stacking defects. Using in situ studies, combining atomic resolution of transmission electron microscopy and controlled VLS crystal growth using metal organic chemical vapor deposition, we investigate the simplest achievable change in atomic layer stacking–single twinned layers formed in GaAs. Using Au-assisted GaAs nanowires of various diameters, we study the formation of individual layers with atomic resolution to reveal the growth difference in forming a twin defect. We determine that the formation of a twinned layer occurs significantly more slowly than that of a normal crystal layer. To understand this, we conduct thermodynamic modeling and determine that the propagation of a twin is limited by the energy cost of forming the twin interface. Finally, we determine that the slower propagation of twinned layers increases the probability of additional layers nucleating, such that multiple layers grow simultaneously. This observation challenges the current understanding that continuous uniform epitaxial growth, especially in the case of liquid-metal assisted nanowires, proceeds one single layer at a time and that its progression is limited by the nucleation rate.

Gaussian processes are powerful non-parametric probabilistic models for stochastic functions. However, the direct implementation entails a complexity that is computationally intractable when the number of observations is large, especially when estimated with fully Bayesian methods such as Markov chain Monte Carlo. In this paper, we focus on a low-rank approximate Bayesian Gaussian processes, based on a basis function approximation via Laplace eigenfunctions for stationary covariance functions. The main contribution of this paper is a detailed analysis of the performance, and practical recommendations for how to select the number of basis functions and the boundary factor. Intuitive visualizations and recommendations, make it easier for users to improve approximation accuracy and computational performance. We also propose diagnostics for checking that the number of basis functions and the boundary factor are adequate given the data. The approach is simple and exhibits an attractive computational complexity due to its linear structure, and it is easy to implement in probabilistic programming frameworks. Several illustrative examples of the performance and applicability of the method in the probabilistic programming language Stan are presented together with the underlying Stan model code., Comment: 27 pages, 18 figures

Hematopoietic stem cell transplantation (HSCT) requires an intensive pre- and post-procedure course that leads to symptoms including fatigue, nausea/vomiting, and pain, all of which interfere significantly with activities of daily living. These symptoms place a substantial burden on patients during the time period surrounding transplant as well as during long-term recovery. The MD Anderson Symptom Inventory (MDASI) is a symptom-reporting survey that has been successfully used in adult patients with cancer and may have utility in the adolescent and young adult (AYA) population. At the Children’s Cancer Hospital at MD Anderson Cancer Center, we adopted a modified version of the MDASI, the MDASI-adolescent (MDASI-Adol), as a standard of care for clinical practice in assessing the symptom burden of patients in the peri-transplant period. We then conducted a retrospective chart review to describe the clinical utility of implementing this symptom-screening tool in AYA patients admitted to our pediatric stem cell transplant service. Here, we report our findings on the symptom burden experienced by pediatric and AYA patients undergoing stem cell transplantation as reported on the MDASI-Adol. Our study confirmed that the MDASI-Adol was able to identify a high symptom burden related to HSCT in the AYA population and that it can be used to guide symptom-specific interventions prior to transplant and during recovery. Implementing a standard symptom-screening survey proved informative to our clinical practice and could mitigate treatment complications and alleviate symptom burden.

ObjectiveTo understand which outcome measures patients and their families, health care providers, and researchers prioritize after aneurysmal subarachnoid hemorrhage (aSAH).MethodsWe conducted a cross-sectional q-sort survey with participants from three key stakeholder groups. Potential outcomes were identified from interviews and focus groups. Participants were purposively sampled to achieve diversity based on stakeholder group, geography, and profession. Respondents sorted 27 outcomes in a quasi-normally distributed grid (Q-Sort) from most to least important. Principal components analysis was used to determine similarities in the way participants sorted the outcome measures resulting in distinct groupings. Overall rankings were also reported.Results112 participants were invited. 70 responded and 64 participants from 25 different countries completed a Q-sort. Balanced stakeholder representation was achieved. Five distinct patterns were identified based on survival, pathophysiological, psychological, resource use, and functional outcome measures. Quality of life as reported by the patient was the highest ranked outcome measure followed by independence and functional measures. Survival and biomedical outcomes were ranked in the middle and cost measures last.ConclusionsIn this diverse sample of key stakeholders, we characterized several distinct perspectives with respect to outcome measure selection in aSAH. We did not identify a clear pattern of opinion based on stakeholder group or other participant characteristics. Patient-reported measure of quality of life was ranked the most important overall with function and independence also highly rated. These results will assist study design and inform efforts to improve outcome selection in aSAH research.

Purpose: In this study we aimed to estimate the effectiveness of pharmacological, nutraceutical, and phytopharmaceutical treatments on CRF. Methods: Ovid MEDLINE, Ovid Embase, Ovid Psych info, CINHAHL and Cochrane Library databases were searched up to 30 September 2021. Randomized controlled trials of pharmacological, nutraceutical and phytopharmaceutical interventions for treatment of CRF for at least one week duration and have used valid tool to assess severity of CRF as a primary or secondary outcome were considered. Results: 32 eligible studies (4896 patients) were reviewed. For the overall meta-analysis, the random effect models yielded the treatment effect (95% CI) of −0.29 (−0.48,−0.09), p < 0.001. The meta-analysis did not show significant reduction of CRF with treatment with ginseng (n = 6), guarana (n = 3), megestrol (n = 2), mistletoe (n = 3), psychostimulants (n = 14), SSRI/antidepressants (n = 2). Corticosteroids (n = 2) showed significant reduction in CRF with treatment effects of 0.94 (−1.21, −0.67), p

PURPOSE Many hospitals have established goals-of-care programs in response to the coronavirus disease 2019 pandemic; however, few have reported their outcomes. We examined the impact of a multicomponent interdisciplinary goals-of-care program on intensive care unit (ICU) mortality and hospital outcomes for medical inpatients with cancer. METHODS This single-center study with a quasi-experimental design included consecutive adult patients with cancer admitted to medical units at the MD Anderson Cancer Center, TX, during the 8-month preimplementation (May 1, 2019-December 31, 2019) and postimplementation period (May 1, 2020-December 31, 2020). The primary outcome was ICU mortality. Secondary outcomes included ICU length of stay, hospital mortality, and proportion/timing of care plan documentation. Propensity score weighting was used to adjust for differences in potential covariates, including age, sex, cancer diagnosis, race/ethnicity, and Sequential Organ Failure Assessment score. RESULTS This study involved 12,941 hospitalized patients with cancer (pre n = 6,977; post n = 5,964) including 1,365 ICU admissions (pre n = 727; post n = 638). After multicomponent goals-of-care program initiation, we observed a significant reduction in ICU mortality (28.2% v 21.9%; change −6.3%, 95% CI, −9.6 to −3.1; P = .0001). We also observed significant decreases in length of ICU stay (mean change −1.4 days, 95% CI, −2.0 to −0.7; P < .0001) and in-hospital mortality (7% v 6.1%, mean change −0.9%, 95% CI, −1.5 to −0.3; P = .004). The proportion of hospitalized patients with an in-hospital do-not-resuscitate order increased significantly from 14.7% to 19.6% after implementation (odds ratio, 1.4; 95% CI, 1.3 to 1.5; P < .0001), and do-not-resuscitate order was established earlier (mean difference −3.0 days, 95% CI, −3.9 to −2.1; P < .0001). CONCLUSION This study showed improvement in hospital outcomes and care plan documentation after implementation of a system-wide, multicomponent goals-of-care intervention.

Background In the ESC guidelines for chronic heart failure an electrocardiogram (ECG) is part of the diagnostic set-up (1). A normal ECG makes the diagnosis unlikely. But can a normal ECG exclude heart failure with reduced left ventricular ejection fraction (HFrEF) and be a gatekeeper to echocardiography? Methods Patients referred from primary care to the cardiac outpatient clinic with suspicion of heart failure were consecutively included in the study, during a period of one year. With the referral from primary care was included an ECG which was assessed by a senior cardiologist and divided into two groups: 1) Patients with normal ECG; 2) Patients with pathologically ECG. Subsequently, an echocardiographic examination was performed in a blinded fashion and left ventricular ejection fraction (LVEF) was measured. Results Overall, 403 patients were included in the study. A normal ECG was present in 155 (38%) patients and a pathological ECG was present in 248 (62%) patients. In total, an echocardiographic examination identified 55 (14%) patients with an LVEF below 60% and 33 patients (8%) with LVEF below 50%. In patients with a normal ECG, only two patients had heart failure with a mildly reduced ejection fraction (41–49%), Figure 1. Thus, the ECG had a sensitivity of 94% and a negative predictive value of 99%, Figure 2. Conclusion A normal electrocardiogram has a high diagnostic sensitivity and negative predictive value for excluding heart failure with reduced LVEF and could be a gatekeeping tool in the prioritization of patients referred to echocardiography examination from primary care. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Department of Cardiovascular research, OUH, Svendborg Hospital

There has been limited new high-level evidence generated to guide aneurysmal subarachnoid hemorrhage (aSAH) management in the past decade. The choice of outcome measures used in aSAH clinical trials may be one of the factors hindering progress. In this narrative review we consider the current process for determining “what” to measure in aSAH and identify some of the shortcomings of these approaches. A consideration of the unique clinical course of aSAH is then discussed and how this impacts on selecting the best timepoints to assess change in the chosen constructs. We also review the how to critically appraise different measurement instruments and some of the issues with how these are applied in the context of aSAH. We conclude with current initiatives to improve outcome selection in aSAH and future directions in the research agenda.