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PURPOSE To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. METHODS Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. RESULTS The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. CONCLUSION Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

Purpose: To describe a patient with sickle cell disease, a prothrombotic disorder, who underwent successful embryo cryopreservation for the purposes of fertility preservation prior to hematopoietic stem cell transplant. Methods: To report a successful case of gonadotropin stimulation and embryo cryopreservation using the aromatase inhibitor letrozole to maintain low serum estradiol to minimize thrombotic risk in a patient with sickle cell disease (SCD) and history of retinal artery thrombosis planning hematopoietic stem cell transplant (HSCT). The patient was given letrozole (5 mg daily) as well as prophylactic enoxaparin while undergoing gonadotropin stimulation with an antagonist protocol to preserve fertility prior to HSCT. After the oocyte retrieval, letrozole was continued for one additional week. Results: The patient’s peak serum estradiol concentration was 172 pg/mL during gonadotropin stimulation. Ten mature oocytes were retrieved and a total of 10 blastocysts were cryopreserved. The patient required pain medication and intravenous fluids after oocyte retrieval due to pain but had significant improvement at the scheduled post-operative day one follow-up. No embolic events occurred during stimulation or 6 months thereafter. Conclusion: The utilization of definitive treatment for SCD with stem cell transplant is increasing. We successfully used letrozole to maintain low serum estradiol during gonadotropin stimulation along with prophylactic enoxaparin in a patient with SCD to minimize her risk of thrombosis. This approach will allow patients planning definitive treatment with stem cell transplant the opportunity to preserve their fertility safely.

Nitrogenase catalyzes the multi-electron reduction of dinitrogen to ammonia. Electron transfer in the catalytic protein (MoFeP) proceeds through a unique [8Fe-7S] cluster (P-cluster) to the active site (FeMoco). In the reduced, all-ferrous (PN) state, the P-cluster is coordinated by six cysteine residues. Upon two-electron oxidation to the P2+ state, the P-cluster undergoes conformational changes in which a highly conserved oxygen-based residue (a Ser or a Tyr) and a backbone amide additionally ligate the cluster. Previous studies of Azotobacter vinelandii (Av) MoFeP revealed that when the oxygen-based residue, βSer188, was mutated to a non-coordinating residue, Ala, the P-cluster became redox-labile and reversibly lost two of its eight Fe centers. Surprisingly, the Av strain with a MoFeP variant that lacked the serine ligand (Av βSer188Ala MoFeP) displayed the same diazotrophic growth and in vitro enzyme turnover rates as wild-type Av MoFeP, calling into question the necessity of this conserved ligand for nitrogenase function. Based on these observations, we hypothesized that βSer188 plays a role in protecting the P-cluster under non-ideal conditions. Here, we investigated the protective role of βSer188 both in vivo and in vitro by characterizing the ability of Av βSer188Ala cells to grow under suboptimal conditions (high oxidative stress or Fe limitation) and by characterizing the ability of Av βSer188Ala MoFeP to be mismetallated in vitro. Our results demonstrate that βSer188 (1) increases Av cell survival upon exposure to oxidative stress in the form of hydrogen peroxide, (2) is necessary for efficient Av diazotrophic growth under Fe-limiting conditions, and (3) may protect the P-cluster from metal exchange in vitro. Taken together, our findings suggest a structural adaptation of nitrogenase to protect the P-cluster via Ser ligation, which is a previously unidentified functional role of the Ser residue in redox proteins and adds to the expanding functional roles of non-Cys ligands to FeS clusters.

While biomedical and life science research have embraced interdisciplinarity as the means to solving pressing 21st century complex challenges, interdisciplinarity in undergraduate education has been more difficult to implement. As a consequence, disciplinary rather than interdisciplinary capstones have become ubiquitous. Disciplinary capstones are valuable for students because they enable them to integrate knowledge and skills within the discipline, but they are also limiting because the integration is within rather than across disciplines. In contrast to a capstone, which involves a single discipline, interdisciplinary capstones require two or more disciplines to combine and integrate across disciplinary boundaries. Interdisciplinarity, where two of more disciplines come together, is difficult to implement in the biomedical and life science curricula because student majors and finances are administered in ways, which reinforce institutional organization of schools and faculties and prevent collaboration. Here in this "idea to explore" we provide an interdisciplinary capstone model where students enroll in disciplinary courses, but then these disciplinary courses and students collaborate on interdisciplinary real-world problems. This interdisciplinary capstone model was implemented across two diverse and large biomedical and life science schools within two faculties in a research intensive, metropolitan university. This approach allows for integration of the biomedical, social and ethical perspectives required when solving problems in the real world, such as COVID-19. Interdisciplinary learning also better prepares students for higher degree research and future careers. Overcoming disciplinary curriculum silos and faculty barriers is critical if we are to meet expectations of acquiring interdisciplinarity as a key competency.

Root exudates and rhizosheaths of attached soil are important features of growing roots. To elucidate factors involved in rhizosheath formation, wild-type (WT) barley (Hordeum vulgare L. cv. Pallas) and a root hairless mutant, bald root barley (brb), were investigated with a combination of physiological, biochemical, and immunochemical assays. When grown in soil, WT barley roots bound ∼5-fold more soil than brb per unit root length. High molecular weight (HMW) polysaccharide exudates of brb roots had less soil-binding capacity than those of WT root exudates. Carbohydrate and glycan monoclonal antibody analyses of HMW polysaccharide exudates indicated differing glycan profiles. Relative to WT plants, root exudates of brb had reduced signals for arabinogalactan-protein (AGP), extensin, and heteroxylan epitopes. In contrast, the root exudate of 2-week-old brb plants contained ∼25-fold more detectable xyloglucan epitope relative to WT. Root system immunoprints confirmed the higher levels of release of the xyloglucan epitope from brb root apices and root axes relative to WT. Epitope detection with anion-exchange chromatography indicated that the increased detection of xyloglucan in brb exudates was due to enhanced abundance of a neutral polymer. Conversely, brb root exudates contained decreased amounts of an acidic polymer, with soil-binding properties, containing the xyloglucan epitope and glycoprotein and heteroxylan epitopes relative to WT. We, therefore, propose that, in addition to physically structuring soil particles, root hairs facilitate rhizosheath formation by releasing a soil-binding polysaccharide complex.

Microstigmus Ducke (Hymenoptera, Apoidea, Crabronidae, Pemphredoninae) is an intriguing genus of wasp, particularly interesting for the study of social evolution as it contains the only species of apoid wasps known to exhibit eusocial behaviours. Thus far, data concerning the genetics and biology of sociality in Microstigmus are restricted to just two species. Through behavioural observations and genetic analyses, we here present a detailed report on the nesting biology and social organisation of a third species, Microstigmus rosae. Our results indicate that M. rosae nests are founded by a single female and social groups appear when emerging female offspring remain on the natal nests as helpers. Adult females mass provision their offspring and developmental data are consistent with sequential brood production, an average egg laying interval of 10 days and a brood developmental period of more than 35 days. Social group formation is atypical, with 20% of nests containing up to a maximum of four adult females and two males. Adult group size is positively correlated with the number of brood in a nest, but negatively correlated with per capita brood. The sex investment ratio was female biased. Our findings support several theories concerning the behavioural characteristics thought to be important for transitions towards sociality, namely: high genetic relatedness generated by monogamous matrifilial associations, hygienic behaviour and the potential for direct reproduction. In contrast, one hypothesised trait, progressive provisioning, is notably absent, highlighting the need for investigations into the significance of post-provisioning parental care for offspring survival in this genus.

The immune system requires an adequate supply of nutrients, although current dietary recommendations may not account for optimal immune function in healthy adults. Nutrient inadequacies due to the growing influence of the western diet pose a risk for immune dysfunction. This review aims to determine the beneficial effects of supplementing: dietary fats, nutrients that modulate gut microbiota, and specific micronutrients, on systemic immune functions (concentrations of plasma cytokines, antibodies and acute phase proteins) during health and acute inflammatory conditions, including COVID-19. We discussed micronutrients (selenium, zinc and vitamin D) with compelling evidence supporting immunomodulatory properties. Additionally, the synergistic effects of physical activity and dietary interventions on systemic immune markers are explored. Briefly, evidence suggests that dietary consumption of monounsaturated (oleic and palmitoleic acids) and omega-3 polyunsaturated fatty acids (eicosapentaenoic and docosahexaenoic acids) promotes anti-inflammatory properties. Food sources (fiber, prebiotics, probiotics, omega-3) and patterns (Mediterranean diet) increase the production of short-chain fatty acids, beneficially altering gut microbiota composition, which subsequently enhances the immunomodulatory properties of circulating immune cells. A positive synergistic role of nutrient supplementation (omega-3 and fiber) and physical activity on circulating C-reactive protein and interleukin-6 levels have been observed. Lastly, omega-3 supplementation during COVID-19 infection may reduce circulating C-reactive protein and pro-inflammatory cytokines and improves pain and fatigue symptoms. This review highlights recent findings that support the beneficial role of specific nutrients in promoting systemic immune function in healthy adults. However, to establish specific dietary recommendations to support optimal immune function, more research is required.

Elsinoë species are the causal agents of scab and spot diseases on many economically important plant species. Diagnosis based on symptomology is often problematic, and traditional methods are not appropriate as Elsinoë spp. are notoriously difficult to isolate and slow growing. Three Elsinoë species that infect Citrus are regulated as quarantine organisms within the European Union. Reliable and fast detection of Elsinoë species on citrus fruit is essential for effective phytosanitary control. In this study, a multiplex real-time PCR was designed for rapid and sensitive detection of Elsinoë species, and validation was focused on citrus fruit. The test was specific to the Elsinoë genus when tested against a range of nontarget pathogens and had the ability to detect all three regulated Elsinoë species on Citrus. The test also proved highly sensitive, with a limit of detection of 12 fg of DNA per reaction. This new test can be used as a tool in the diagnostic process for the rapid and sensitive detection of Elsinoë pathogens on symptomatic plant material. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

In addition to the selective importance of interspecific morphological variation, ontogenetic morphological variation may reflect different selective regimes to which successive developmental stages are subjected. The typical body form of carcharhiniform sharks is considered relatively conserved, yet sharks exhibit a wide range of body sizes and shapes, representing adaptations to distinct ecological niches. Previous investigations of ontogenetic shifts in shark body form have provided evidence for both isometric and allometric changes, depending on the morphological characters and species investigated. These findings have led to suggestions of a relationship between body size and allometric growth in sharks. In this study we present evidence of ontogenetic allometric shifts in two species of carcharhiniform sharks (Sphyrna lewini and Rhizoprionodon longurio) from novel measurements. Our results are generally consistent with previous suggestions of body form conservatism across shark phylogeny, yet also suggest potential selective factors underlying observed instances of ontogenetic allometric shifts, and highlight where additional studies are required. We propose the ‘allometric niche shift’ hypothesis for interspecific differences in scaling trends, suggesting that long-distance movements and ontogenetic trophic niche shifts represent key drivers of allometry in sharks.

Background Joint modelling combines two or more statistical models to reduce bias and increase efficiency. As the use of joint modelling increases it is important to understand how and why it is being applied to heart failure research. Methods A systematic review of major medical databases of studies which used joint modelling within heart failure alongside an exemplar; joint modelling repeat measurements of serum digoxin with all-cause mortality using data from the Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure (DIG) trial. Results Overall, 28 studies were included that used joint models, 25 (89%) used data from cohort studies, the remaining 3 (11%) using data from clinical trials. 21 (75%) of the studies used biomarkers and the remaining studies used imaging parameters and functional parameters. The exemplar findings show that a per unit increase of square root serum digoxin is associated with the hazard of all-cause mortality increasing by 1.77 (1.34–2.33) times when adjusting for clinically relevant covariates. Conclusion Recently, there has been a rise in publications of joint modelling being applied to heart failure. Where appropriate, joint models should be preferred over traditional models allowing for the inclusion of repeated measures while accounting for the biological nature of biomarkers and measurement error.

Chronic pain affects 30-40% of individuals with sickle cell disease (SCD) and impairs patient functioning. Clinically meaningful, practical, and valid assessment tools for investigation, evaluation and management of chronic pain are limited, representing a barrier for advancing SCD care. We sought to determine whether patient-reported outcomes (PROs) show preliminary construct validity in identifying individuals with SCD who were a priori defined as suggestive of having chronic pain based on previously published criteria. All individuals completed PROMIS domains Pain Interference, Pain Behavior, Pain Quality (Nociceptive, Neuropathic), Fatigue, Sleep Disturbance, Depression, Anxiety; ASCQ-Me domains Pain Impact and Emotional Impact; and painDETECT questionnaire. Thirty-three adults living with SCD were enrolled, 42.4% had chronic pain. Pain-related PROs scores distinctly differentiated individuals with chronic pain from those without. Individuals with chronic pain had significantly worse pain-related PROs scores: PROMIS Pain Interference 64.2 vs 54.3, p

In January 2022, a group of experts came together to discuss current perspectives and future directions in nutritional immunology as part of a symposium organized by the Canadian Nutrition Society. Objectives included (1) creating an understanding of the complex interplay between diet and the immune system from infants through to older adults, (2) illustrating the role of micronutrients that are vital to the immune system, (3) learning about current research comparing the impact of various dietary patterns and novel approaches to reduce inflammation, autoimmune conditions, allergies, and infections, and (4) discussing select dietary recommendations aimed at improving disease-specific immune function. The aims of this review are to summarize the symposium and to identify key areas of research that require additional exploration to better understand the dynamic relationship between nutrition and immune function.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic. As immunity to endemic human coronaviruses (i.e. NL63 or OC43) wanes leading to re-infection, it was unknown if SARS-CoV-2 immunity would also decline permitting repeat infections. Recent case reports confirm previously infected individuals can become re-infected; however, re-infection may be due to heterogeneity in the initial infection or the host immune response, or may be the result of infection with a variant strain that escapes pre-existing immunity. To control these variables, we utilized the Syrian hamster model to evaluate the duration of immunity and susceptibility to re-infection with SARS-CoV-2. Hamsters were given a primary mock or SARS-CoV-2 infection (culture media or 10

We examined the effects of exercise on prostate cancer-specific anxiety, fear of cancer progression, quality of life and psychosocial outcomes in patients with prostate cancer on active surveillance.The ERASE (Exercise during Active Surveillance for Prostate Cancer) Trial randomized 52 patients with prostate cancer undergoing active surveillance to high-intensity interval training (HIIT, 26 patients) or usual care (UC, 26 patients). The HIIT group performed a 12-week, thrice weekly, supervised, aerobic HIIT program. The UC group did not exercise. Patient-reported outcomes were assessed at baseline and after intervention, including prostate cancer-specific anxiety (Memorial Anxiety Scale for Prostate Cancer), fear of cancer progression (Fear of Cancer Recurrence Inventory), prostate cancer symptoms (Expanded Prostate Cancer Index Composite), quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core) and psychological health outcomes (eg fatigue, stress and self-esteem). Analysis of covariance was used to compare between-group differences.Fifty of 52 participants (96%) completed patient-reported outcome assessments at 12 weeks. Adherence to HIIT was 96%. Compared to UC, HIIT significantly improved total prostate cancer-specific anxiety (adjusted between-group mean difference -2.7, 95% confidence interval, range -5.0 to -0.4, p=0.024), as well as the fear of progression subscale (p=0.013), hormonal symptoms (p=0.005), perceived stress (p=0.037), fatigue (p=0.029) and self-esteem (p=0.007).A 12-week supervised HIIT program may improve prostate cancer-specific anxiety, fear of cancer progression, hormone symptoms, stress, fatigue and self-esteem in men with prostate cancer on active surveillance. Larger trials are needed to confirm the effects of HIIT on patient-reported outcomes in the active surveillance setting.

Aim: To report the experience of chronic pain participants after a well-formulated ketogenic diet (WFKD) or whole-food diet (WFD). The quantitative outcomes for this trial have been published separately (clinical trial registration number ACTRN12620000946910). Patients & methods: The experience of 24 participants was evaluated after 12 and 24 weeks of dietary intervention using survey responses and open questions. Results & conclusion: Retention rates for the WFKD and WFD groups were 93 and 89%, respectively. Average adherence to the WFKD was 82% and to the WFD was 87%. The WFKD enjoyment was rated at 66 and 81% for the WFD group. The ease of adhering to the diet varied more widely for the WFKD group. Barriers included knowledge integration, time management, navigating social food environments and emotional attachment to eliminated foods. Facilitators included structured support and coaching, and comprehensive learning materials. The WFKD was shown to be a feasible and effective treatment option for chronic pain.

Human milk is a highly complex liquid food tailor-made to match an infant's needs. Beyond documented positive effects of breastfeeding on infant and maternal health, there is increasing evidence that milk constituents also impact child neurodevelopment. Non-nutrient milk bioactives would contribute to the (long-term) development of child cognition and behavior, a process termed 'Lactocrine Programming'. In this review we discuss the current state of the field on human milk composition and its links with child cognitive and behavioral development. To promote state-of-the-art methodologies and designs that facilitate data pooling and meta-analytic endeavors, we present detailed recommendations and best practices for future studies. Finally, we determine important scientific gaps that need to be filled to advance the field, and discuss innovative directions for future research. Unveiling the mechanisms underlying the links between human milk and child cognition and behavior will deepen our understanding of the broad functions of this complex liquid food, as well as provide necessary information for designing future interventions., All authors participated in the four-day hybrid meeting on ‘Lactational Programming: joining forces to optimize research on how maternal milk composition influences child cognition and behavior’ (Zeist, the Netherlands, 16-19 November 2020), which was financed by an Early Career Partnership 2020 Grant of the Royal Netherlands Academy of Arts and Sciences (awarded to Beijers). Funding sources for individual authors: Netherlands Organization for Scientific Research VICI grant (016.Vici.185.038-to de Weerth), The National Center for Advancing Translational Sciences Clinical Science and Translational Award (UL1TR001863-to Dettmer), NWO Food Cognition and Behaviour (057-14-003-to Korosi), Turku University Foundation, Maire Taponen Foundation and Finnish Psychiatry Foundation (-to Aatsinki), Polish National Science Centre OPUS grant (2015/17/B/NZ8/02436 -to Ziomkiewicz), Canadian Research Chair in Human Nutrition and Metabolism and funding from Natural Science and Engineering Council of Canada NSERC (RGPIN-2017-04746-to Field), The USDA National Institute of Food and Agriculture Hatch Project (1021411-to Slupsky), USDA NRI (2007-35203-18098 and 2013-67016-20523-to Bartol), Spanish Ministry of Science and Innovation grant (PID2019-105606RB-I00-to Rodríguez), UC San Diego Chair of Collaborative Human Milk Research, endowed by the Family Larsson-Rosenquist Foundation, Switzerland (-to Bode), Wellcome Trust (220225/Z/20/Z-to Moore), Tier 2 Canada Research Chair and Fellow in the CIFAR Humans and the Microbiome Program, Canadian Institutes of Health Research (CIHR), Research Manitoba, the Canada Foundation for Innovation, the Bill and Melinda Gates Foundation, the Manitoba Children’s Hospital Foundation, Prolacta Biosciences, Mitacs, CIFAR, and the Garfield G. Weston Foundation (-to Azad), CIHR Vanier Canada Graduate Scholarship (-to Turner), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC starting grant, no. 639226-to Collado), Netherlands Organization for Scientific Research VENI grant (016.195.197-to Beijers).

Bioactive ingredients for infant formula have been sought to reduce disparities in health outcomes between breastfed and formula-fed infants. Traditional food safety methodologies have limited ability to assess some bioactive ingredients. It is difficult to assess the effects of nutrition on the infant immune system because of coincident developmental adaptations to birth, establishment of the microbiome and introduction to solid foods, and perinatal environmental factors. An expert panel was convened to review information on immune system development published since the 2004 Institute of Medicine report on evaluating the safety of new infant formula ingredients and to recommend measurements that demonstrate the safety of bioactive ingredients intended for that use. Panel members participated in a 2-d virtual symposium in November 2020 and in follow-up discussions throughout early 2021. Key topics included identification of immune system endpoints from nutritional intervention studies, effects of human milk feeding and human milk substances on infant health outcomes, ontologic development of the infant immune system, and microbial influences on tolerance. The panel explored how "nonnormal" conditions such as preterm birth, allergy, and genetic disorders could help define developmental immune markers for healthy term infants. With consideration of breastfed infants as a reference, ensuring proper control groups, and attention to numerous potential confounders, the panel recommended a set of standard clinical endpoints including growth, response to vaccination, infection and other adverse effects related to inflammation, and allergy and atopic diseases. It compiled a set of candidate markers to characterize stereotypical patterns of immune system development during infancy, but absence of reference ranges, variability in methods and populations, and unreliability of individual markers to predict disease prevented the panel from including many markers as safety endpoints. The panel's findings and recommendations are applicable for industry, regulatory, and academic settings, and will inform safety assessments for immunomodulatory ingredients in foods besides infant formula.

International audience; pDynamo3 is the first formal version of the Dynamo molecular modeling and simulation library that is written in Python 3. It follows from the previous pDynamo versions written in Python 2, the first of which was released in 2007. Both pDynamo and its predecessor, fDynamo, were designed with the aim of providing easy-to-use and flexible frameworks for performing molecular simulations at an atomistic level with a special emphasis on those employing hybrid quantum chemical and molecular mechanical potential methods. Although the use of pDynamo3 is quite similar to that of pDynamo2, it has added significant new capability and also undergone extensive restructur-ing that will make it much easier to extend with new functionality. The pDynamo3 code is issued under the GNU general public license at https://github.com/pdynamo/pDynamo3 with additional information on the pDynamo website https:www.pdynamo.org.

Background Patients with sickle cell disease (SCD) have vaso-occlusive crises (VOCs). Infusion centers (ICs) are alternatives to emergency department (ED) care and may improve patient outcomes. Objective To assess whether care in ICs or EDs leads to better outcomes for the treatment of uncomplicated VOCs. Design Prospective cohort. (ClinicalTrials.gov: NCT02411396). Setting 4 U.S. sites, with recruitment between April 2015 and December 2016. Participants Adults with SCD living within 60 miles of a study site. Measurements Participants were followed for 18 months after enrollment. Outcomes of interest were time to first dose of parenteral pain medication, whether pain reassessment was completed within 30 minutes after the first dose, and patient disposition on discharge from the acute care visit. Treatment effects for ICs versus EDs were estimated using a time-varying propensity score adjustment. Results Researchers enrolled 483 participants; the 269 who had acute care visits on weekdays are included in this report. With inverse probability of treatment-weighted adjustment, the mean time to first dose was 62 minutes in ICs and 132 minutes in EDs; the difference was 70 minutes (95% CI, 54 to 98 minutes; E-value, 2.8). The probability of pain reassessment within 30 minutes of the first dose of parenteral pain medication was 3.8 times greater (CI, 2.63 to 5.64 times greater; E-value, 4.7) in the IC than the ED. The probability that a participant's visit would end in admission to the hospital was smaller by a factor of 4 (0.25 [CI, 0.18 to 0.33]) with treatment in an IC versus an ED. Limitation The study was restricted to participants with uncomplicated VOCs. Conclusion In adults with SCD having a VOC, treatment in an IC is associated with substantially better outcomes than treatment in an ED. Primary funding source Patient-Centered Outcomes Research Institute.

Background: Identifying genetic variants that affect the level of cell cycle reentry and establishing the degree of cell cycle progression in those variants could help guide development of therapeutic interventions aimed at effecting cardiac regeneration. We observed that C57Bl6/NCR (B6N) mice have a marked increase in cardiomyocyte S-phase activity after permanent coronary artery ligation compared with infarcted DBA/2J (D2J) mice. Methods: Cardiomyocyte cell cycle activity after infarction was monitored in D2J, (D2J×B6N)-F1, and (D2J×B6N)-F1×D2J backcross mice by means of bromodeoxyuridine or 5-ethynyl-2′-deoxyuridine incorporation using a nuclear-localized transgenic reporter to identify cardiomyocyte nuclei. Genome-wide quantitative trait locus analysis, fine scale genetic mapping, whole exome sequencing, and RNA sequencing analyses of the backcross mice were performed to identify the gene responsible for the elevated cardiomyocyte S-phase phenotype. Results: (D2J×B6N)-F1 mice exhibited a 14-fold increase in cardiomyocyte S-phase activity in ventricular regions remote from infarct scar compared with D2J mice (0.798±0.09% versus 0.056±0.004%; P P Tnni3k (troponin I-interacting kinase) is expressed in B6N hearts but not in D2J hearts. Transgenic expression of TNNI3K in a D2J genetic background results in elevated cardiomyocyte S-phase activity after injury. Cardiomyocyte S-phase activity in both Tnni3k-expressing and Tnni3k-nonexpressing mice results in the formation of polyploid nuclei. Conclusions: These data indicate that Tnni3k expression increases the level of cardiomyocyte S-phase activity after injury.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic and multiple vaccines have been developed and authorized for human use. While these vaccines reduce disease severity, they do not prevent infection allowing SARS-CoV-2 to continue to spread and evolve. To confer protection against infection and limit transmission, vaccines must be developed that induce mucosal immunity in the respiratory tract. Therefore, we performed proof-of-principle pre-clinical vaccine and challenge studies with a virus-particle mimicking intranasal vaccine against SARS-CoV-2. The vaccine candidate consisted of the self-assembling 60-subunit I3-01 protein scaffold covalently decorated with the SARS-CoV-2 receptor binding domain (RBD) using the SpyCatcher-SpyTag system. We verified the intended antigen display features by reconstructing the I3-01 scaffold to 3.4A using cryo-EM, and established RBD decoration through both SDS-PAGE and negative stain TEM. Using this RBD grafted SpyCage scaffold (RBD+SpyCage), we performed two vaccination studies in Syrian hamsters using an intranasal prime and boost vaccine regiment followed by SARS-CoV-2 challenge. The initial study focused on assessing the immunogenicity of RBD+SpyCage, which indicated that vaccination of hamsters induced a non-neutralizing antibody response that enhanced viral clearance but did not prevent infection. In an expanded study, we demonstrated that covalent bonding of RBD to the scaffold was required to induce an antibody response. Consistent with the initial study, animals vaccinated with RBD+SpyCage more rapidly cleared SARS-CoV-2 from both the upper and lower respiratory tract, whereas admixtures of SpyCage and RBD, or either components alone did not. These findings demonstrate the intranasal SpyCage vaccine platform can induce protection against SARS-CoV-2 and, with additional modifications to improve immunogenicity, is a versatile and adaptable system for the development of intranasal vaccines targeting respiratory pathogens.

Complex patterns of genome and life-history evolution associated with the end-Cretaceous (K– Pg) mass extinction event limit our understanding of the early evolutionary history of crown group birds [1-9]. Here, we assess molecular heterogeneity across living birds using a technique enabling inferred sequence substitution models to transition across the history of a clade [10]. Our approach identifies distinct and contrasting regimes of molecular evolution across exons, introns, untranslated regions, and mitochondrial genomes. Up to fifteen shifts in the mode of avian molecular evolution map to rapidly diversifying clades near the Cretaceous-Palaeogene boundary, demonstrating a burst of genomic disparity early in the evolutionary history of crown birds [11-13]. Using simulation and machine learning techniques, we show that shifts in developmental mode [14] or adult body mass [4] best explain transitions in the mode of nucleotide substitution. These patterns are related, in turn, to macroevolutionary shifts in the allometric scaling relationship between basal metabolic rate and body mass [15, 16]. In agreement with theoretical predictions, this scaling relationship appears to have weakened across the end-Cretaceous transition. Overall, our study provides evidence that the Chicxulub bolide impact [17] triggered integrated patterns of evolution across avian genomes, physiology, and life history that structured the evolutionary potential of modern birds.

This chapter evaluates the U.S. Synthetic Rubber Program, which was designed as a response to the loss of Southeast Asian rubber imports during World War II. The initiative was hampered both by flawed design and by prewar denialism that the United States would or should become involved in the war, which led to delays in facilities construction. The U.S. Synthetic Rubber Program started late, failed to meet production targets before the last quarter of 1943, produced an imperfect substitute for natural rubber, and involved hundreds of millions of dollars of unnecessary expenditure. In the wake of a politicized battle over what feedstock should be used in the program, and after his veto of the Rubber Supply Act of 1942, President Roosevelt appointed a committee and instructed it to examine the perilous economic, military, and political situation in which the country then found itself. The chapter then discusses the crisis that brought the committee into existence and the substance of its September 1942 Report of the Rubber Survey Committee, referred to as the Survey Committee Report. It looks at the attempts to develop alternative plant-based sources of latex; the program's emphasis on petroleum; and the nationwide program of gas rationing to save rubber.

Many believe that despite its destructive character, war ultimately boosts long-term economic growth. For the United States, this view is often supported by appeal to the experience of the Second World War, understood as a triumph of both production and productivity. This book shows that between 1941 and 1945, manufacturing productivity actually declined, depressed by changes in the output mix and resource shocks from enemy action, including curtailed access to natural rubber and, on the Eastern Seaboard, petroleum. The war forced a shift away from producing goods in which the country had a great deal of experience toward those in which it had little. Learning by doing was only a partial counterbalance to the intermittent idleness and input hoarding that characterized a shortage economy and dragged down productivity. The conflict distorted human and physical capital accumulation and once it ended, America stopped producing most of the new goods. The war temporarily shut down basic scientific research and the ongoing development of civilian goods. U.S. world economic dominance in 1948, the book shows, was due less to the experience of making war goods and more to the country's productive potential in 1941.

This chapter provides an overview of the economic consequences of U.S. mobilization for World War II. It begins by describing the state of the U.S. economy in 1941. The record of U.S. manufacturing output during the war is indubitably impressive. In contrast, the record with respect to productivity is disappointing, whether one looks at the manufacturing sector alone or the total economy, and whether one considers only the period of war mobilization and demobilization, or the years that followed as well. This book argues that total factor productivity in manufacturing fell during the war because the conflict forced a wrenching shift away from products and processes in which manufacturers had a great deal of experience toward the production of goods in which they had little. The chapter explains economic growth and growth accounting with regard to U.S. mobilization for World War II. It also assesses two earlier transitions which provide insight into the adverse initial consequences of process and product mix changeovers. The first involves the electrification of the internal distribution of power within factories during the early decades of the twentieth century. A second and particularly interesting case is Ford's 1927 shift from producing Model Ts to Model As.

This chapter explores the challenges to the petroleum industry during World War II, the most serious of which came from German U-boats, whose activities directly and indirectly threatened the manufacturing heartland of the country and the strategic capabilities of the United States and its allies. Dealing with East Coast supply was primarily a distribution challenge, not a production or refining problem. The chapter then looks at how U-boat predation led to the construction of two pipelines from East Texas to the Northeast (Big Inch and Little Big Inch pipelines), financed by the government. After a two-year postwar hiatus, the pipelines were again used, but at that point to transport natural gas. Ultimately, the history of the petroleum industry between 1941 and 1945 is consistent with declining productivity in U.S. manufacturing. In responding to neither of the sector's main challenges did the exigencies of war lead to breakthrough technologies in the exploration for, production of, or refining of oil.

This chapter investigates how shortages of materials and subassemblies, aggravated by producer hoarding, drove the priorities unemployment that was a signature feature of production during the first half of U.S. participation in the war. After 1943, severe labor shortage and a secondary product composition effect added to the mix. Throughout the war, these strains periodically caused productive capacity to remain idle, sometimes for extended periods. The chapter then looks at the 1943 minutes of the meetings of the War Production Board. It also considers the push for national service legislation, which was seen by advocates as a move in the direction of more equal sacrifice and as a partial solution to labor shortages and high turnover in industry. Moreover, the chapter studies the manpower policies of the Selective Service System.

This chapter reflects on the attribution of positive long-term supply-side benefits to U.S. economic mobilization for World War II. The use of the word “miracle” in descriptions of U.S. manufacturing during World War II celebrates the ability of the country to produce thousands of Liberty ships, tens of thousands of tanks, hundreds of thousands of aircraft, jeeps, trucks, and guns to supply the soldiers, sailors, and airmen of the United States and its allies while at the same time sustaining domestic consumption. World War II did leave significant institutional, normative, and economic legacies for the United States. The war was not, however, associated with a political revolution or fundamental changes in the instrumentalities of government. The chapter then looks at the historiography of U.S. military conflict and economic growth, considering the American Civil War. Both World War II and the American Civil War reduced potential output while under way.

This chapter addresses the narrative of learning by doing, which is central to the claim that World War II production experience had persisting positive effects on aggregate supply. References almost always begin with the Liberty ships and go on to cite examples of the inverse relationship between cumulated output and unit labor requirements for B-24s, C-47s, or Oerlikon antiaircraft guns. To the extent these oft-reported gains were real, they were, nonetheless, associated with striking declines in overall manufacturing productivity during the war. The chapter explores why this was so and also why that experience did little to boost either military or civilian capability after the war. The main explanation for the limited postwar impact is that the manufacture of most of the products in question ceased even before the end of the conflict or, if not, soon after. In contrast with what was true during the war, postwar military hardware had limited production runs and much higher costs per unit. Moreover, learning to produce a sequence of military durables had an important opportunity cost: it disrupted advance in the manufacture of metal-intensive consumer durables. The chapter then considers the legacy of wartime capital accumulation.

This chapter assesses whether distribution internalized within the military generated learning of persisting relevance for the postwar period. There is a plausible case that, as in the instance of manufacturing, it did not, that the wartime experience was sui generis and without lasting implications for the golden age of U.S. economic growth (1948–73). There is also a counter case suggesting that the logistics experience, even if not a postcard illustration of efficiency and high productivity, nevertheless laid the groundwork for and stimulated advances in the postwar period, particularly in civilian distribution. Ultimately, U.S. total factor productivity growth rates after 1973 proved disappointing, with the exception of the information technology boom between 1995 and 2005. U.S. manufacturing continued to shrink as a proportion of the economy, and the most progressive sectors of the economy were those that produced the information technology and exploited it to manage distribution networks.

BACKGROUND Sickle cell disease (SCD) was first recognized in 1910 and identified as a genetic condition in 1949. However, there is not a universal clinical registry that can be used currently to estimate prevalence. The Sickle Cell Data Collection (SCDC) program, funded by the Centers for Disease Control and Prevention, funds state-level grantees to compile data within their states from various sources including administrative claims to identify individuals with SCD. The performance of the SCDC administrative claims case definition has been validated in a pediatric population with SCD, but it has not been tested in adults. OBJECTIVE The objective of our study is to evaluate the discriminatory ability of the SCDC administrative claims case definition to accurately identify adult SCD cases using Medicaid insurance claims data. METHODS Our study uses Medicaid claims data in combination with hospital-based medical record data from the Alabama (AL), Georgia (GA), and Wisconsin (WI) SCDC programs to identify individuals 18 years of age or older meeting the SCDC administrative claims case definition. In order to validate this definition, our study included only those subjects that were identified in both Medicaid and the partnering clinical institution. We used clinical laboratory tests and diagnostic algorithms to determine the true SCD status of this subset. Positive predictive values (PPV) are reported overall and by state under several scenarios. RESULTS There were 1,219 individuals (354 from AL and 865 from GA) who were identified using a 5-year time period. The 5-year time period yielded a PPV of 88.4% (91% for data from AL, 87% for data from GA), when only using data with lab-confirmed (gold standard) cases as true positives. With a narrower time period (3-year period) and data from three states (AL, GA and WI), there were a total of 1,432 individuals from these states included in our study. The 3-year time period PPV overall was 89.4% (92%, 93% and 81% for data from AL, GA and WI respectively) when only considering lab-confirmed cases as true cases CONCLUSIONS Adults identified as having SCD from administrative claims data using the SCDC case definition have a high probability of truly having the disease especially if those hospitals have active SCD programs. Administrative claims are thus a valuable data source to identify adults with SCD in a state and understand their epidemiology and healthcare service utilization. CLINICALTRIAL