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Background Hospitalization rates after transcatheter aortic valve replacement (TAVR) remain high, given the age and comorbidities of patients undergoing TAVR. To better understand the impact of TAVR on hospitalization, we sought to compare hospitalization rates before and after TAVR and to examine if underlying patient comorbidities are associated with a differential effect of TAVR on hospitalizations. Methods and Results We used the Nationwide Readmissions Database to identify patients who underwent TAVR. As Nationwide Readmissions Database data do not cross over calendar years, we limited our index admission to hospitalizations during April to September of each calendar year to allow 90 days of observation before and after TAVRs. We calculated the daily risk of all‐cause hospitalization and used a mixed‐effects logistic regression model to explore interactions between patient characteristics, TAVR, and hospitalization risk. Among 39 249 patients who underwent TAVR in 2014 to 2017 (median age, 82 years [interquartile range, 76–87 years]; 45.7% women), 32.0% had at least one hospitalization in the 90 days before TAVR compared with 23.2% in the 90 days post‐TAVR (relative reduction, 27.5%; P

Objective This study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.Study design Retrospective discovery and longitudinal confirmation.Setting Maternity units from two US hospitals.Participants Six previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.Outcome measures Biomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.Results Our discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks’ gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.Conclusions Our study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

Introdução: A Púrpura Trombocitopênica Idiopática (PTI) é uma desordem da hemostasia caracterizada por plaquetopenia na ausência de outras condições sistêmicas associadas. Em adultos, a doença possui caráter crônico, porém na infância costuma ser aguda, tanto que maioria dos casos responde bem sem a necessidade de medicação. A prevalência em adultos é maior do que em crianças, sendo mais comum no sexo feminino em proporção de 3 a 4:1, sendo o tratamento com uso de corticoide, glicocorticoide ou anticorpo monoclonal. Objetivo: Este trabalho tem como proposição relatar um caso de uma paciente pediátrica com PTI crônica, não responsiva a corticoide, Imunoglobulina e Eletrombopague, com plaquetopenia importante sendo submetida a extrações de dentes decíduos em ambiente hospitalar. Relato de caso: Paciente do sexo feminino com 8 anos de idade, pesando 29 kg em uso somente de Vitamina C com média das contagens de plaquetas de 7 mil/mm³(variando de 1 a 15 mil/mm³) desde janeiro de 2019 a julho de 2021, com histórico de infecção odontogênica em lado direito inferior ocorrido em maio de 2020 tratado somente com antibiótico na época. No exame clínico e radiografia panorâmica observou-se a necessidade de extrações dos dentes decíduos 55 e 84, devido a extensas lesões de cáries e radiolúcidez. O caso clínico foi discutido com a equipe médica e programado a internação da paciente subsequente a solicitação de exames complementares e suporte sistêmico no pré-operatório, pós-operatório e medidas hemostáticas locais no momento cirúrgico e pós-cirúrgico. O protocolo seguido foi, prednisona 2mg/kg por 10 dias com intervenção no sétimo dia, início de amoxicilina 500 mg por 7 dias com início um dia antes do procedimento. O exame hematológico de um dia antes da intervenção mostrou 15 mil/mm³, sendo solicitado transfusão de concentrados de plaquetas de 3 unidade no pré e pós-operatório. As extrações dos dentes 55 e 84 foram realizadas em um único momento sob anestesia local, por técnica infiltrativa com lidocaína e adrenalina, com 2 tubetes injetados, por técnica fechada, curetagem das lesões, inserção de esponja hemostática, sutura com fio de nylon e curativo com ácido tranexâmico comprimido de 100 mg e gaze no local operado. Paciente no pós-operatório de 1 dia evoluiu sem dor e sem sangramento ativo, porém foi vista uma queda importante na contagem de plaquetas para 8 mil/mm³, sendo solicitado mais 3 unidades de plaquetas e manutenção dos cuidados locais com curativos de ácido tranexâmico a cada 6 horas por mais 6 dias. Paciente seguiu com alta hospitalar 48 horas de pós-operatório na ausência de queixas de dor e sangramento na região. Paciente retornou em 7 dias com aumento de 10 mil/mm³plaquetas, sem sangramento, sem dor e realização da remoção de suturas. Paciente retornou em 15 dias com queda de 2 mil/mm³ plaquetas, sem sangramento, sem dor e formação de tecido na região operada. Conclusão: O caso relatado mostra a importância da equipe multidisciplinar no atendimento seguro de pacientes com risco de sangramento. Para casos complexos com risco de sangramento em procedimentos odontológicos invasivos, sugere-se o planejamento com a equipe médica, internação da paciente e utilização de meios hemostáticos locais.

Background In aortic valve disease, the relationship between claims‐based frailty indices (CFIs) and validated measures of frailty constructed from in‐person assessments is unclear but may be relevant for retrospective ascertainment of frailty status when otherwise unmeasured. Methods and Results We linked adults aged ≥65 years in the US CoreValve Studies (linkage rate, 67%; mean age, 82.7±6.2 years, 43.1% women), to Medicare inpatient claims, 2011 to 2015. The Johns Hopkins CFI, validated on the basis of the Fried index, was generated for each study participant, and the association between CFI tertile and trial outcomes was evaluated as part of the EXTEND‐FRAILTY substudy. Among 2357 participants (64.9% frail), higher CFI tertile was associated with greater impairments in nutrition, disability, cognition, and self‐rated health. The primary outcome of all‐cause mortality at 1 year occurred in 19.3%, 23.1%, and 31.3% of those in tertiles 1 to 3, respectively (tertile 2 versus 1: hazard ratio, 1.22; 95% CI, 0.98–1.51; P=0.07; tertile 3 versus 1: hazard ratio, 1.73; 95% CI, 1.41–2.12; P

Abstract Background In urban Kenya, couples face a wide variety of choices for delivery options; however, many women end up delivering in different facilities from those they had intended while pregnant. One potential consequence of this is delivering in facilities that do not meet minimum quality standards and lack the capacity to provide treatment for obstetric and neonatal complications. Methods This study investigated why women in peri-urban Nairobi, Kenya deliver in facilities they had not intended to use. We used 60 in-depth audio-recorded interviews in which mothers shared their experiences 2–6 months after delivery. Descriptive statistics were used to summarize socio-demographic characteristics of participants. Qualitative data were analyzed in three steps i) exploration and generation of initial codes; ii) searching for themes by gathering coded data that addressed specific themes; and iii) defining and naming identified themes. Verbatim excerpts from participants were provided to illustrate study findings. The Health Belief Model was used to shed light on individual-level drivers of delivery location choice. Results Findings show a confluence of factors that predispose mothers to delivering in unintended facilities. At the individual level, precipitate labor, financial limitations, onset of pain, complications, changes in birth plans, undisclosed birth plans, travel during pregnancy, fear of health facility providers, misconception of onset of labor, wrong estimate of delivery date, and onset of labor at night, contributed to delivery at unplanned locations. On the supply side, the sudden referral to other facilities, poor services, wrong projection of delivery date, and long distance to chosen delivery facility, were factors in changes in delivery location. Lack of transport discouraged delivery at a chosen health facility. Social influences included others’ perspectives on delivery location and lack of aides/escorts. Conclusions Results from this study suggest that manifold factors contribute to the occurrence of women delivering in facilities that they had not intended during pregnancy. Future studies should consider whether these changes in delivery location late in pregnancy contribute to late facility arrival and the use of lower quality facilities. Deliberate counseling during antenatal care regarding birth plans is likely to encourage timely arrival at facilities consistent with women’s preferences.

Abstract Background Disseminating care guidelines into clinical practice remains challenging, partly due to inadequate evidence on how best to help clinics incorporate new guidelines into routine care. This is particularly true in safety net community health centers (CHCs). Methods This pragmatic comparative effectiveness trial used a parallel mixed methods design. Twenty-nine CHC clinics were randomized to receive increasingly intensive implementation support (implementation toolkit (arm 1); toolkit + in-person training + training webinars (arm 2); toolkit + training + webinars + offered practice facilitation (arm 3)) targeting uptake of electronic health record (EHR) tools focused on guideline-concordant cardioprotective prescribing for patients with diabetes. Outcomes were compared across study arms, to test whether increased support yielded additive improvements, and with 137 non-study CHCs that share the same EHR as the study clinics. Quantitative data from the CHCs’ EHR were used to compare the magnitude of change in guideline-concordant ACE/ARB and statin prescribing, using adjusted Poisson regressions. Qualitative data collected using diverse methods (e.g., interviews, observations) identified factors influencing the quantitative outcomes. Results Outcomes at CHCs receiving higher-intensity support did not improve in an additive pattern. ACE/ARB prescribing did not improve in any CHC group. Statin prescribing improved overall and was significantly greater only in the arm 1 and arm 2 CHCs compared with the non-study CHCs. Factors influencing the finding of no additive impact included: aspects of the EHR tools that reduced their utility, barriers to providing the intended implementation support, and study design elements, e.g., inability to adapt the provided support. Factors influencing overall improvements in statin outcomes likely included a secular trend in awareness of statin prescribing guidelines, selection bias where motivated clinics volunteered for the study, and study participation focusing clinic staff on the targeted outcomes. Conclusions Efforts to implement care guidelines should: ensure adaptability when providing implementation support and conduct formative evaluations to determine the optimal form of such support for a given clinic; consider how study data collection influences adoption; and consider barriers to clinics’ ability to use/accept implementation support as planned. More research is needed on supporting change implementation in under-resourced settings like CHCs. Trial registration ClinicalTrials.gov, NCT02325531. Registered 15 December 2014.

Abstract Background Tumors can employ different mechanisms to evade immune surveillance and function. Overexpression of co-inhibitory ligands that bind to checkpoint molecules on the surface of T-cells can greatly impair the function of latter. TIGIT (T cell immunoreceptor with Ig and ITIM domains) is such a co-inhibitory receptor expressed by T and NK cells which, upon binding to its ligand (e.g., CD155), can diminish cytokine production and effector function. Additionally, the absence of positive co-stimulation at the tumor site can further dampen T-cell response. Methods As T-cell genetic engineering has become clinically-relevant in the recent years, we devised herein a strategy aimed at enhancing T-cell anti-tumor function by diverting T-cell coinhibitory signals into positive ones using a chimeric costimulatory switch receptor (CSR) composed of the TIGIT exodomain fused to the signaling domain of CD28. Results After selecting an optimized TIGIT-28 CSR, we co-transduced it along with tumor-specific TCR or CAR into human T-cells. TIGIT-28-equipped T-cells exhibited enhanced cytokine secretion and upregulation of activation markers upon co-culture with tumor cells. TIGIT-28 enhancing capability was also demonstrated in an original in vitro model of T-cell of hypofunction induction upon repetitive antigen exposure. Finally, we tested the function of this molecule in the context of a xenograft model of established human melanoma tumors and showed that TIGIT-28-engineered human T-cells demonstrated superior anti-tumor function. Conclusion Overall, we propose that TIGIT-based CSR can substantially enhance T-cell function and thus contribute to the improvement of engineered T cell-based immunotherapy.

Abstract Background Access-related infections are a major cause of morbidity and mortality in haemodialysis patients. Our goal was to decrease the rate of these infections by implementing an intervention and surveillance program. Methods This intervention took place in two haemodialysis units (Units A and B) and was a joint effort by the haemodialysis staff and the unit for infection prevention and control. It included reviewing the work methods and work space, observations on compliance with standard precautions and handling of the vascular access, creating a checklist and a designated kit for handling the vascular access and prospective surveillance of access-related infections. Results During a nine-year period, the haemodialysis units A and B treated 4471 and 7547 patients (mean number of patients per year: 497 (range 435–556) and 839 (range 777–1055), respectively). For most patients, the procedure was done through an arteriovenous fistula (66.7%, range 50.3–81.5%). The access-related infection rate decreased significantly in both haemodialysis units: from 3 to 0.9% (trend: p

Abstract Background Targeting epitopes derived from neo-antigens (or “neo-epitopes”) represents a promising immunotherapy approach with limited off-target effects. However, most peptides predicted using MHC binding prediction algorithms do not induce a CD8 + T cell response, and there is a crucial need to refine the predictions to readily identify the best antigens that could mediate T-cell responses. Such a response requires a high enough number of epitopes bound to the target MHC. This number is correlated with both the peptide-MHC binding affinity and the number of peptides reaching the ER. Beyond this, the response may be affected by the properties of the neo-epitope mutated residues. Methods Herein, we analyzed several experimental datasets from cancer patients to elaborate better predictive algorithms for T-cell reactivity to neo-epitopes. Results Indeed, potent classifiers for epitopes derived from neo-antigens in melanoma and other tumors can be developed based on biochemical properties of the mutated residue, the antigen expression level and the peptide processing stage. Among MHC binding peptides, the present classifiers can remove half of the peptides falsely predicted to activate T cells while maintaining the absolute majority of reactive peptides. Conclusions The classifier properties further highlight the contribution of the quantity of peptides reaching the ER and the mutation type to CD8 + T cell responses. These classifiers were then validated on neo-antigens obtained from other datasets, confirming the validity of our prediction. Algorithm Availability: http://peptibase.cs.biu.ac.il/Tcell_predictor/ or by request from the authors as a standalone code.

Most theories of numerical cognition assume that the perception of a quantity is independent of that which the quantity describes (termed an abstract quantity representation). Beck’s cognitive theory of depression, in contrast, assumes that depressed individuals maintain negative perceptual biases and that depressed individuals’ perception of quantity will be dependent on that which the quantity describes. Here, we explore the nature of quantity representations by assessing whether level of depression and valence of events influences individuals’ perceptions of numerical quantities. In a number bisection task, we presented participants with three quantities: one associated with the time until a positive event, one associated with the time until a negative event, and a target number. The participant was asked to judge whether the quantity denoted by the target number was closer to the time until the positive or negative event. Results indicated that event valence influenced the perception of quantity and this perceptual bias interacted with the level of depression. Thus, these findings indicate that quantity representations are malleable and are represented non-abstractly in the brain.

Polar amplification – the phenomenon where external radiative forcing produces a larger change in surface temperature at high latitudes than the global average – is a key aspect of anthropogenic climate change, but its causes and consequences are not fully understood. The Polar Amplification Model Intercomparison Project (PAMIP) contribution to the sixth Coupled Model Intercomparison Project (CMIP6; Eyring et al., 2016) seeks to improve our understanding of this phenomenon through a coordinated set of numerical model experiments documented here. In particular, PAMIP will address the following primary questions: (1) what are the relative roles of local sea ice and remote sea surface temperature changes in driving polar amplification? (2) How does the global climate system respond to changes in Arctic and Antarctic sea ice? These issues will be addressed with multi-model simulations that are forced with different combinations of sea ice and/or sea surface temperatures representing present-day, pre-industrial and future conditions. The use of three time periods allows the signals of interest to be diagnosed in multiple ways. Lower-priority tier experiments are proposed to investigate additional aspects and provide further understanding of the physical processes. These experiments will address the following specific questions: what role does ocean–atmosphere coupling play in the response to sea ice? How and why does the atmospheric response to Arctic sea ice depend on the pattern of sea ice forcing? How and why does the atmospheric response to Arctic sea ice depend on the model background state? What have been the roles of local sea ice and remote sea surface temperature in polar amplification, and the response to sea ice, over the recent period since 1979? How does the response to sea ice evolve on decadal and longer timescales? A key goal of PAMIP is to determine the real-world situation using imperfect climate models. Although the experiments proposed here form a coordinated set, we anticipate a large spread across models. However, this spread will be exploited by seeking “emergent constraints” in which model uncertainty may be reduced by using an observable quantity that physically explains the intermodel spread. In summary, PAMIP will improve our understanding of the physical processes that drive polar amplification and its global climate impacts, thereby reducing the uncertainties in future projections and predictions of climate change and variability.

Abstract Background The use of implementation strategies is an active and purposive approach to translate research findings into routine clinical care. The Expert Recommendations for Implementing Change (ERIC) identified and defined discrete implementation strategies, and Proctor and colleagues have made recommendations for specifying operationalization of each strategy. We use empirical data to test how the ERIC taxonomy applies to a large dissemination and implementation initiative aimed at taking cardiac prevention to scale in primary care practice. Methods EvidenceNOW is an Agency for Healthcare Research and Quality initiative that funded seven cooperatives across seven regions in the USA. Cooperatives implemented multi-component interventions to improve heart health and build quality improvement capacity, and used a range of implementation strategies to foster practice change. We used ERIC to identify cooperatives’ implementation strategies and specified the actor, action, target, dose, temporality, justification, and expected outcome for each. We mapped and compiled a matrix of the specified ERIC strategies across the cooperatives, and used consensus to resolve mapping differences. We then grouped implementation strategies by outcomes and justifications, which led to insights regarding the use of and linkages between ERIC strategies in real-world scale-up efforts. Results Thirty-three ERIC strategies were used by cooperatives. We identified a range of revisions to the ERIC taxonomy to improve the practical application of these strategies. These proposed changes include revisions to four strategy names and 12 definitions. We suggest adding three new strategies because they encapsulate distinct actions that were not described in the existing ERIC taxonomy. In addition, we organized ERIC implementation strategies into four functional groupings based on the way we observed them being applied in practice. These groupings show how ERIC strategies are, out of necessity, interconnected, to achieve the work involved in rapidly taking evidence to scale. Conclusions Findings of our work suggest revisions to the ERIC implementation strategies to reflect their utilization in real-work dissemination and implementation efforts. The functional groupings of the ERIC implementation strategies that emerged from on-the-ground implementers will help guide others in choosing among and linking multiple implementation strategies when planning small- and large-scale implementation efforts. Trial registration Registered as Observational Study at www.clinicaltrials.gov (NCT02560428).

CD45, the predominant transmembrane tyrosine phosphatase in leukocytes, is required for the efficient induction of T cell receptor signaling and activation. We recently reported that the CD45-intracellular signals in peripheral blood mononuclear cells (PBMCs) of triple negative breast cancer (TNBC) patients are inhibited. We also reported that C24D, an immune modulating therapeutic peptide, binds to CD45 on immune-suppressed cells and resets the functionality of the immune system via the CD45 signaling pathway. Various studies have demonstrated that also viruses can interfere with the functions of CD45 and that patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are immune-suppressed. Given the similarity between the role of CD45 in viral immune suppression and our findings on TNBC, we hypothesized that the C24D peptide may have a similar “immune-resetting” effect on PBMCs from COVID-19 patients as it did on PBMCs from TNBC patients. We tested this hypothesis by comparing the CD45/TCR intracellular signaling in PBMCs from ten COVID-19 patients vs. PBMCs from ten healthy volunteers. Herein, we report our findings, demonstrating the immune reactivating effect of C24D via the phosphorylation of the tyrosine 505 and 394 in Lck, the tyrosine 493 in ZAP-70 and the tyrosine 172 in VAV-1 proteins in the CD45 signaling pathway. Despite the relatively small number of patients in this report, the results demonstrate that C24D rescued CD45 signaling. Given the central role played by CD45 in the immune system, we suggest CD45 as a potential therapeutic target.

Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.

It has been postulated that glyphosate (G) or its commercial formulation Roundup (R) might lead to male fertility impairment. In this study, we investigated the possible effects of G or R treatment of juvenile male rats on blood-testis barrier function and on adult male sperm production. Pups were randomly assigned to the following groups: control group (C), receiving water; G2 and G50 groups, receiving 2 and 50 mg/kg/day G respectively; and R2 and R50 groups receiving 2 and 50 mg/kg/day R respectively. Treatments were performed orally from postnatal day (PND) 14 to 30, period of life that is essential to complete a functional blood-testis barrier. Evaluation was done on PND 31. No differences in body and testis weight were observed between groups. Testis histological analysis showed disorganized seminiferous epithelium, with apparent low cellular adhesion in treated animals. Blood-testis barrier permeability to a biotin tracer was examined. A significant increase in permeable tubules was observed in treated groups. To evaluate possible mechanisms that could explain the effects on blood-testis barrier permeability, intratesticular testosterone levels, androgen receptor expression, thiobarbituric acid reactive substances (TBARS) and the expression of intercellular junction proteins (claudin11, occludin, ZO-1, connexin43, 46, and 50 which are components of the blood-testis barrier) were examined. No modifications in the above-mentioned parameters were detected. To evaluate whether juvenile exposure to G and R could have consequences during adulthood, a set of animals of the R50 group was allowed to grow up until PND 90. Histological analysis showed that control and R50 groups had normal cellular associations and complete spermatogenesis. Also, blood-testis barrier function was recovered and testicular weight, daily sperm production, and epididymal sperm motility and morphology did not seem to be modified by juvenile treatment. In conclusion, the results presented herein show that continuous exposure to low doses of G or R alters blood-testis barrier permeability in juvenile rats. However, considering that adult animals treated during the juvenile stage showed no differences in daily sperm production compared with control animals, it is feasible to think that blood-testis barrier impairment is a reversible phenomenon. More studies are needed to determine possible damage in the reproductive function of human juvenile populations exposed to low doses of G or R.

Volumetric muscle loss (VML) is the acute loss of muscle mass due to trauma. Such injuries occur primarily in the extremities and are debilitating, as there is no clinical treatment to restore muscle function. Pro-inflammatory advanced glycation end-products (AGEs) and the soluble receptor for advanced glycation end-products (RAGE) are known to increase in acute trauma patient’s serum and are correlated with increased injury severity. However, it is unclear whether AGEs and RAGE increase in muscle post-trauma. To test this, we used decellularized muscle matrix (DMM), a pro-myogenic, non-immunogenic extracellular matrix biomaterial derived from skeletal muscle. We delivered adipose-derived stromal cells (ASCs) and primary myoblasts to support myogenesis and immunomodulation (N = 8 rats/group). DMM non-seeded and seeded grafts were compared to empty defect and sham controls. Then, 56 days after surgery muscle force was assessed, histology characterized, and protein levels for AGEs, RAGE, p38 MAPK, and myosin heavy chains were measured. Overall, our data showed improved muscle regeneration in ASC-treated injury sites and a regulation of RAGE and p38 MAPK signaling, while myoblast-treated injuries resulted in minor improvements. Taken together, these results suggested that ASCs combined with DMM provides a pro-myogenic microenvironment with immunomodulatory capabilities and indicates further exploration of RAGE signaling in VML.

This paper presents the results of a study that used a speeded counting task to adjudicate between two competing theories of how perceptual representations of visual objects are derived. Boolean map (BM) theory assumes that there are strict limits on conscious awareness, such that we only have serial access to features on the same dimension (e.g., red and green). This theory contrasts with views that emphasize the early grouping of features, and which assume that feature processing is interactive and underpins figure/ground segregation as a necessary precursor to object perception. To test between these theories, we report performance in a speeded counting task in which participants were asked to judge which of two shapes was more prevalent. Displays contained squares and circles that appeared in either of two colors, with color and shape distinctions either perfectly correlated (i.e., compatible) or not (i.e., incompatible). BM theory predicts no influence of the relative coincidence of color and shape on the identification of the more prevalent shape. In contrast, grouping theory predicts that performance will be better when the color/shape distinction is compatible than when it is incompatible. Our data strongly support the grouping theory predictions. We conclude that the primary constraints on how visual objects are accessed are the number and kind of groupings that are recovered, not the number of feature maps consulted.

One of the most pressing challenges facing food systems in Africa is ensuring availability of a healthy and sustainable diet to 2.4 billion people by 2050. The continent has struggled with development challenges, particularly chronic food insecurity and pervasive poverty. In Africa's food systems, fish and other aquatic foods play a multifaceted role in generating income, and providing a critical source of essential micronutrients. To date, there are no estimates of investment and potential returns for domestic fish production in Africa. To contribute to policy debates about the future of fish in Africa, we applied the International Model for Policy Analysis of Agriculture Commodities and Trade (IMPACT) to explore two Pan-African scenarios for fish sector growth: a business-as-usual (BAU) scenario and a high-growth scenario for capture fisheries and aquaculture with accompanying strong gross domestic product growth (HIGH). Post-model analysis was used to estimate employment and aquaculture investment requirements for the sector in Africa. Africa's fish sector is estimated to support 20.7 million jobs in 2030, and 21.6 million by 2050 under the BAU. Approximately 2.6 people will be employed indirectly along fisheries and aquaculture value chains for every person directly employed in the fish production stage. Under the HIGH scenario, total employment in Africa's fish food system will reach 58.0 million jobs, representing 2.4% of total projected population in Africa by 2050. Aquaculture production value is estimated to achieve US$ 3.3 billion and US$ 20.4 billion per year under the BAU and HIGH scenarios by 2050, respectively. Farm-gate investment costs for the three key inputs (fish feeds, farm labor, and fish seed) to achieve the aquaculture volumes projected by 2050 are estimated at US$ 1.8 billion per year under the BAU and US$ 11.6 billion per year under the HIGH scenario. Sustained investments are critical to sustain capture fisheries and support aquaculture growth for food system transformation towards healthier diets.

Summary: Background: The association of air pollution with multiple adverse health outcomes is becoming well established, but its negative economic impact is less well appreciated. It is important to elucidate this impact for the states of India. Methods: We estimated exposure to ambient particulate matter pollution, household air pollution, and ambient ozone pollution, and their attributable deaths and disability-adjusted life-years in every state of India as part of the Global Burden of Disease Study (GBD) 2019. We estimated the economic impact of air pollution as the cost of lost output due to premature deaths and morbidity attributable to air pollution for every state of India, using the cost-of-illness method. Findings: 1·67 million (95% uncertainty interval 1·42–1·92) deaths were attributable to air pollution in India in 2019, accounting for 17·8% (15·8–19·5) of the total deaths in the country. The majority of these deaths were from ambient particulate matter pollution (0·98 million [0·77–1·19]) and household air pollution (0·61 million [0·39–0·86]). The death rate due to household air pollution decreased by 64·2% (52·2–74·2) from 1990 to 2019, while that due to ambient particulate matter pollution increased by 115·3% (28·3–344·4) and that due to ambient ozone pollution increased by 139·2% (96·5–195·8). Lost output from premature deaths and morbidity attributable to air pollution accounted for economic losses of US$28·8 billion (21·4–37·4) and $8·0 billion (5·9–10·3), respectively, in India in 2019. This total loss of $36·8 billion (27·4–47·7) was 1·36% of India's gross domestic product (GDP). The economic loss as a proportion of the state GDP varied 3·2 times between the states, ranging from 0·67% (0·47–0·91) to 2·15% (1·60–2·77), and was highest in the low per-capita GDP states of Uttar Pradesh, Bihar, Rajasthan, Madhya Pradesh, and Chhattisgarh. Delhi had the highest per-capita economic loss due to air pollution, followed by Haryana in 2019, with 5·4 times variation across all states. Interpretation: The high burden of death and disease due to air pollution and its associated substantial adverse economic impact from loss of output could impede India's aspiration to be a $5 trillion economy by 2024. Successful reduction of air pollution in India through state-specific strategies would lead to substantial benefits for both the health of the population and the economy. Funding: UN Environment Programme; Bill & Melinda Gates Foundation; and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.

Does the recent electoral success of far-right populists represent a mere rejection of the political and economic status quo, or has it revealed deeper cultural divides? Historically, demographic cleavages have been poor predictors of vote choice and partisanship in Latin America. However, during Brazil’s 2018 presidential election campaign, right-wing candidate Jair Bolsonaro fomented conflict across lines of gender, race, and religion. We argue that his candidacy activated latent, previously unexploited grievances in the electorate. Using survey data from an original five-wave online panel conducted between July 2018 and January 2019, we examine the effect of demographic cleavages on presidential vote choice. In stark contrast to prior elections, we find clear evidence of demographic divides in 2018, partially mediated by issue positions. Bolsonaro’s campaign and subsequent election thus appear to have created new identity-based alignments in Brazil’s electorate. Our findings shed further light on the global resurgence of the far right, suggesting that far-right candidates can attract new bases of support through demographic polarization, exploiting differences in values and issue preferences by gender, race, ethnicity, and religion.

Breast cancer subtypes have not shown significant response to current immunomodulatory therapies. Although most subtypes are treatable, triple negative breast cancer (TNBC), an aggressive highly metastatic cancer, comprising 10–20% of breast cancers, remains an unmet medical need. New strategies are needed in order to overcome flaws in the responsiveness to current TNBC therapies. Our aims were: first, to determine the efficacy of a novel immunomodulatory peptide, C24D, on TNBC and second, to elucidate the molecular mechanism by which C24D induces immune-modulating tumor killing. Using mass spectrometry analysis, we identified CD45 as the C24D binding receptor. In vitro and in vivo TNBC models were used to assess the efficacy of C24D in reversing TNBC-induced immunosuppression and in triggering immune-modulated tumor cell killing. The CD45 signal transduction pathway was evaluated by western blot and FACS analyses. We revealed that addition of PBMCs from healthy female donors to TNBC cells results in a cascade of suppressive CD45 intracellular signals. On binding to CD45’s extra-cellular domain on TNBC-suppressed leukocytes, the C24D peptide re-activates the Src family of tyrosine kinases, resulting in specific tumor immune response. In vitro, immune reactivation by C24D results in an increase of CD69+ T and CD69+ NK cells, triggering specific killing of TNBC cells. In vivo, C24D induced CD8+ and activated CD56+ tumor infiltrated cells, resulting in tumor apoptosis. Our results should renew interest in molecules targeting CD45, such as the C24D peptide, as a novel strategy for TNBC immunotherapy.

Objectives To assess whether the extent of deviation from chronic disease guideline recommendations is more prominent for specific diseases compared with combined-care across multiple conditions among multimorbid patients, and to examine reasons for this deviation.Design A cross-sectional cohort.Setting Multimorbidity care management programme across 11 primary care clinics.Patients Patients aged 45–95 years with at least two common chronic conditions, sampled according to being new (≤6 months) or veteran (≥1 year) to the programme.Main outcome measures Deviation from guideline-recommended care was measured for each patient’s relevant conditions, aggregated and stratified across disease groups, calculated as measures of ‘disease-specific’ guideline deviation and ‘combined-care’ (all conditions) guideline deviation for: atrial fibrillation, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disorder, depression, diabetes, dyslipidaemia, hypertension and ischaemic heart disease. Combined-care deviation was evaluated for its association with specific diseases. Frequencies of previously derived reason types for deviation (biomedical, patient personal and contextual) were reported by nurse care managers, assessed across diseases and evaluated for their association with specific diseases.Results Among 204 patients, disease-specific deviation varied more (from 14.7% to 48.2%) across diseases than combined-care deviation (from 14.7% to 25.6%). Depression and diabetes were significantly associated with more deviation (mean: 6% (95% CI: 2% to 10%) and 5% (95% CI: 2% to 9%), respectively). For some conditions, assessments were among small patient samples. Guideline deviation was often attributed to non-disease-specific reasons, such as physical limitations or care burden, as much as disease-specific reasons, which was reflected in the likelihood for guideline deviation to be due to different types of reasons for some diseases.Conclusions When multimorbid patients are considered in disease groups rather than as ‘whole persons’, as in many quality of care studies, the cross-cutting factors in their care delivery can be missed. The types of reasons more likely to occur for specific diseases may inform improvement strategies.Trial registration number NCT01811173; Pre-results.

Objectives The aim of this study was to develop a single blood test that could determine gestational age and estimate the risk of preterm birth by measuring serum metabolites. We hypothesised that serial metabolic modelling of serum analytes throughout pregnancy could be used to describe fetal gestational age and project preterm birth with a high degree of precision.Study design A retrospective cohort study.Setting Two medical centres from the USA.Participants Thirty-six patients (20 full-term, 16 preterm) enrolled at Stanford University were used to develop gestational age and preterm birth risk algorithms, 22 patients (9 full-term, 13 preterm) enrolled at the University of Alabama were used to validate the algorithms.Outcome measures Maternal blood was collected serially throughout pregnancy. Metabolic datasets were generated using mass spectrometry.Results A model to determine gestational age was developed (R2=0.98) and validated (R2=0.81). 66.7% of the estimates fell within ±1 week of ultrasound results during model validation. Significant disruptions from full-term pregnancy metabolic patterns were observed in preterm pregnancies (R2=−0.68). A separate algorithm to predict preterm birth was developed using a set of 10 metabolic pathways that resulted in an area under the curve of 0.96 and 0.92, a sensitivity of 0.88 and 0.86, and a specificity of 0.96 and 0.92 during development and validation testing, respectively.Conclusions In this study, metabolic profiling was used to develop and test a model for determining gestational age during full-term pregnancy progression, and to determine risk of preterm birth. With additional patient validation studies, these algorithms may be used to identify at-risk pregnancies prompting alterations in clinical care, and to gain biological insights into the pathophysiology of preterm birth. Metabolic pathway-based pregnancy modelling is a novel modality for investigation and clinical application development.

Introduction: Accelerated bone loss and osteoporosis are multifactorial comorbidities related to HIV and its treatments; however, their mechanisms remain elusive. Identifying HIV treatments that are differentially linked to osteoporosis risk, and clinical factors associated with HIV-related osteoporosis may enable optimizing anti-retroviral treatment (ART) and anti-osteoporosis therapy in preventing or treating this debilitating complication. This study aims to evaluate the dynamics of bone turnover markers after initiation of two commonly used antiretroviral regimens. Methods: A prospective matched cohort study. Thirty treatment-naïve male patients (mean age 40 ± 10y) who initiated treatment with truvada (tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)) + raltegravir or TDF/FTC + efavirenz were included in the study. Control group included 15 treatment-naive HIV patients. Serum morning fasting level of P1NP and CTX were measured 0, 1, 6, and 12 months after treatment initiation in the two study groups, and at 0, 6 and 12 months in the control group. Results: In both treatment groups, but not in the control group, both markers increased significantly over time with no difference in BTM between patients treated with raltegravir or efavirenz. Levels of P1NP were statistically higher at 6 and 12 months after treatment initiation in both treatment groups compared to the controls, while CTX during treatment increased in both treatment groups but was significantly higher only in the raltegravir treatment group after 12 months. The ratio of area under the curve of P1NP/CTX correlated with CD4 increment. Conclusions: Treatment initiation with raltegravir or efavirenz combined with TDF/FTC is associated with increased bone turnover. Thus, therapy that optimize bone turnover is needed to reduce bone loss at this vulnerable period and improve long-term bone health.

Proteins are secreted from eukaryotic cells by several mechanisms besides the well-characterized classical secretory system. Proteins destined to enter the classical secretory system contain a signal peptide for translocation into the endoplasmic reticulum. However, many proteins lacking a signal peptide are secreted nonetheless. Contrary to conventional belief, these proteins are not just released as a result of membrane damage leading to cell leakage, but are actively packaged for secretion in alternative pathways. They are called unconventionally secreted proteins, and the best-characterized are from fungi and mammals. These proteins have extracellular functions including cell signaling, immune modulation, as well as moonlighting activities different from their well-described intracellular functions. Among the pathways for unconventional secretion are direct transfer across the plasma membrane, release within plasma membrane-derived microvesicles, use of elements of autophagy, or secretion from endosomal/multivesicular body-related components. We review the fungal and metazoan unconventional secretory pathways and their regulation, and propose experimental criteria to identify their mode of secretion.

ABSTRACT In yeast, many proteins are found in both the cytoplasmic and extracellular compartments, and consequently it can be difficult to distinguish nonconventional secretion from cellular leakage. Therefore, we monitored the extracellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity of intact cells as a specific marker for nonconventional secretion. Extracellular GAPDH activity was proportional to the number of cells assayed, increased with incubation time, and was dependent on added substrates. Preincubation of intact cells with 100 μM dithiothreitol increased the reaction rate, consistent with increased access of the enzyme after reduction of cell wall disulfide cross-links. Such treatment did not increase cell permeability to propidium iodide, in contrast to effects of higher concentrations of reducing agents. An amine-specific membrane-impermeant biotinylation reagent specifically inactivated extracellular GAPDH. The enzyme was secreted again after a 30- to 60-min lag following the inactivation, and there was no concomitant increase in propidium iodide staining. There were about 4 × 104 active GAPDH molecules per cell at steady state, and secretion studies showed replenishment to that level 1 h after inactivation. These results establish conditions for specific quantitative assays of cell wall proteins in the absence of cytoplasmic leakage and for subsequent quantification of secretion rates in intact cells. IMPORTANCE Eukaryotic cells secrete many proteins, including many proteins that do not follow the classical secretion pathway. Among these, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is unexpectedly found in the walls of yeasts and other fungi and in extracellular space in mammalian cell cultures. It is difficult to quantify extracellular GAPDH, because leakage of just a little of the very large amount of cytoplasmic enzyme can invalidate the determinations. We used enzymatic assays of intact cells while also maintaining membrane integrity. The results lead to estimates of the amount of extracellular enzyme and its rate of secretion to the wall in intact cells. Therefore, enzyme assays under controlled conditions can be used to investigate nonconventional secretion more generally.