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Blinatumomab is a CD3 × CD19 antibody approved for adults with B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is not considered myelosuppressive, but significant neutropenia has been seen in practice. We reviewed 95 patients with B-ALL who received blinatumomab at Dana-Farber Cancer Institute between 2015 and 2024. Of these, 71 patients were treated in morphologic remission with absolute neutrophil count (ANC) ≥1 × 109/L, for which 41% experienced grade ≥3 neutropenia and 13% developed ANC <0.1 × 109/L during blinatumomab. Neutropenia occurred more frequently during cycle 2 than cycle 1, and neutropenia did not necessarily portend worse neutropenia in later cycles. Multivariable analysis did not identify concurrent tyrosine kinase inhibitor use as a significant covariate for neutropenia. The nine patients who experienced ANC <0.1 × 109/L did not develop serious infections and received supportive care. Neutropenia occurs frequently and may be severe in patients with B-ALL who receive blinatumomab during remission, but complications appear manageable. [ABSTRACT FROM AUTHOR]

Highly pathogenic avian influenza (HPAI) H5N1 has caused the deaths of more than 100 million birds since 2021, and human cases since 1997 have been associated with significant morbidity and mortality. Given recent detections of HPAI H5N1 in dairy cattle and H5N1 RNA detections in pasteurized retail milk in the United States, we established the pan-Canadian Milk Network in April 2024. Through our network of collaborators from across Canada, retail milk was procured longitudinally, approximately every 2 weeks, and sent to a central laboratory to test for the presence of influenza A virus RNA. Between 29 April and 17 July 2024, we tested 109 retail milk samples from all 10 Canadian provinces (NL, NS, PEI, NB, QC, ON, MB, SK, AB, and BC). All samples tested negative for influenza A virus RNA. This nationwide initiative was established for rapid retail milk screening as per the earliest reports of similar undertakings in the United States. Our independent testing results have aligned with reporting from federal retail milk testing initiatives. Despite no known HPAI infections of dairy cattle in Canada to date, H5N1 poses a significant threat to the health of both humans and other animals. By performing routine surveillance of retail milk on a national scale, we have shown that academic networks and initiatives can rapidly establish nationwide emerging infectious disease surveillance that is cost-effective, standardized, scalable, and easily accessible. Our network can serve as an early detection system to help inform containment and mitigation activities if positive samples are identified and can be readily reactivated should HPAI H5N1 or other emerging zoonotic viruses be identified in agricultural or livestock settings, including Canadian dairy cattle. [ABSTRACT FROM AUTHOR]

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Purpose: To conduct a systematic review on the impacts of using mechanical assistive devices on function, performance in activities and participation of persons with upper extremity impairments, and to synthesize the strengths and limitations of these devices. Method: Three independent reviewers conducted systematic searches of articles published between 2003 and 2023 in Compendex, Inspec, Embase, PubMed/Medline, IEEE Xplore, and Web of Science, as well as manual searches on the RESNA website for conference papers over the same period. The methodological quality of articles was appraised using the QualSyst tool. Results: From the 34 retained studies, 28 mechanical devices were identified and classified into two categories: (1) mobile arm supports (MASs) designed to perform multiple activities, and (2) devices used to assist with a specific activity of daily living (ADL). Overall, MASs helped users to perform manual activities in elevation and/or against gravity. Specific ADL devices allowed users to perform unique activities requiring fine motor skills such as opening a medicine container. Some of these devices have advantages like portability, adaptability, low cost, and ease of use. Limitations most often reported included interference or mobility restraints. Conclusion: This review synthesizes the impacts of mechanical devices on the three domains of the International Classification of Functioning, Disability and Health (ICF) for individuals with upper extremity impairments. Impacts regarding function and performance in activities were more often measured than participation. Future studies should include outcomes related to participation, as taking this aspect into account might favor successful continued use of assistive devices. IMPLICATIONS FOR REHABILITATION: Mechanical mobile arm supports can compensate for upper extremity muscle weakness and help users to perform diverse activities against gravity, including self-care, productivity and leisure activities. Mechanical assistive devices designed for specific activities of daily living (ADLs) can increase users' ability to perform activities requiring manual dexterity and fine motor skills, such as eating, handwriting, performing personal care or playing a musical instrument. Portability, adaptability, low cost, and ease of use are most often reported as strengths of specific ADL devices, while interference and mobility restrictions are aspects that still need to be reduced with respect to mechanical mobile arm supports. [ABSTRACT FROM AUTHOR]

ATP citrate lyase (ACLY), a crucial enzyme in de novo lipid synthesis and histone acetylation, plays a key role in regulating vascular smooth muscle cell (VSMC) proliferation and survival. We found that human coronary and pulmonary artery tissues had up-regulated ACLY expression during vascular remodeling in coronary artery disease and pulmonary arterial hypertension. Pharmacological and genetic inhibition of ACLY in human primary cultured VSMCs isolated from the coronary arteries of patients with coronary artery diseases and from the distal pulmonary arteries of patients with pulmonary arterial hypertension resulted in reduced cellular proliferation and migration and increased susceptibility to apoptosis. These cellular changes were linked to diminished glycolysis, reduced lipid synthesis, impairment in general control nonrepressed protein 5 (GCN5)–dependent histone acetylation and suppression of the transcription factor FOXM1. In vivo studies using a pharmacological inhibitor and VSMC-specific Acly knockout mice showed that ACLY inhibition alleviated vascular remodeling. ACLY inhibition alleviated remodeling in carotid injury and ligation models in rodents and attenuated pulmonary arterial hypertension in Sugen/hypoxia rat and mouse models. Moreover, ACLY inhibition showed improvements in vascular remodeling in human ex vivo models, which included cultured human coronary artery and saphenous vein rings as well as precision-cut lung slices. Our results propose ACLY as a novel therapeutic target for treating complex vascular diseases, offering promising avenues for future clinical intervention. Editor's summary: Cardiovascular diseases are leading causes of mortality, prompting investigation into new therapeutic targets. Grobs et al. focused on ATP citrate lyase (ACLY) for its metabolic and epigenetic roles important for vascular cell proliferation in disease. ACLY was increased in patients with pulmonary arterial hypertension and in animal models. ACLY promoted cellular proliferation, increased acetyl-CoA, altered metabolism, and increased histone acetylation in vitro. These changes were linked to signaling that regulates vascular reprogramming. An ACLY inhibitor and genetic inactivation promoted disease improvement in several rodent models of pulmonary hypertension. The same inhibitor also showed efficacy in damaged human vessel tissue and in human precision-cut lung slices exposed to stress to mimic disease. Together, these data indicate that ACLY may be a target for treating vascular diseases through its regulatory roles. —Brandon Berry [ABSTRACT FROM AUTHOR]

Upper limb impairments, resulting from various neurological and neuromuscular conditions, significantly impact daily activities and limit social participation. Assistive technologies, particularly dynamic arm supports, offer promising solutions to enhance independence for individuals facing these challenges. This paper presents the development of an affordable dynamic arm support, designed with a focus on static balancing. The support utilizes a four-bar linkage mechanism to allow smooth vertical movement while maintaining the orientation of the armrest. Furthermore, the integration of rotational and prismatic joints enhances the device's adaptability, enabling horizontal movements. Through comprehensive mathematical modeling and prototype testing, we introduce a cost-effective arm support that effectively counterbalances the arm's weight, ensuring ease of movement and stability across various spatial orientations. [ABSTRACT FROM AUTHOR]

Abstract The extended endocannabinoid system, also termed endocannabinoidome, participates in multiple metabolic functions in health and disease. Physical activity can both have an acute and chronic impact on endocannabinoid mediators, as does diet. In this crossover randomized controlled study, we investigated the influence of diet on the peripheral response to acute maximal aerobic exercise in a sample of active adult women (n = 7) with no underlying metabolic conditions. We compared the impact of 7-day standardized Mediterranean diet (MedDiet) and control diet inspired by Canadian macronutrient intake (CanDiet) on endocannabinoidome and short-chain fatty acid metabolites post maximal aerobic exercise. Overall, plasmatic endocannabinoids, their congeners and some polyunsaturated fatty acids increased significantly post maximal aerobic exercise upon cessation of exercise and recovered their initial values within 1 h after exercise. Most N-acylethanolamines and polyunsaturated fatty acids increased directly after exercise when the participants had consumed the MedDiet, but not when they had consumed the CanDiet. This impact was different for monoacylglycerol endocannabinoid congeners, which in most cases reacted similarly to acute exercise while on the MedDiet or the CanDiet. Fecal microbiota was only minimally affected by the diet in this cohort. This study demonstrates that endocannabinoidome mediators respond to acute maximal aerobic exercise in a way that is dependent on the diet consumed in the week prior to exercise.

Intro: Population acceptance of vaccination is a fundamental issue for health authorities, including in a department such as French Guiana, which is characterized by more precarious conditions and sometimes limited healthcare capacities. In order to study and monitor the extent of reluctance and to identify factors associated with vaccination intentions we set up a repeated online public survey. The purpose of the survey was to inform public decision-making, contribute to public debate, and provide useful data for research on the determinants associated with vaccine intentions Methods: Four two-week survey waves, including between 1000 and 1400 people, were conducted between March and November 2021. Multifactor analyses characterized populations in terms of perceptions, intentions, and opinions regarding the management of the epidemic in and vaccination. Findings: Vaccination intentions increased slightly from 45.5% in March 2021 to 55.2% of the population in October 2021. Significant geographic disparities were observed ranging from 29.6% to 78.8%. Vaccination intentions against COVID increased with age, socioeconomic level, and confidence in the government and local authorities. Uncertainty about the efficacý of the vaccine, fear of side effects, preference for using traditional remedies, and having been previously infected were among the most cited arguments by vaccine avoiders. Discussion: The study revealed a important reluctance to vaccinate, in a context of low perception of the risk associated with the infection, strong distrust of the health authorities and the government, and a lack of information on the side effects of the vaccine, which is perceived by the Guyanese population as an obstacle to vaccination. The study revealed significant difficulties in changing vaccination intentions over time in the most resistant population groups. Conclusion: The results of these surveys were used to develop a typology of the population and to provide health authorities with useful information in real time to optimize the vaccination campaign.

Intro: The emergence of SARS-CoV-2 was accompanied by great uncertainty regarding the main epidemiological characteristics of the transmission. In a context where epidemiological surveillance was mainly targeted on symptomatic patients, we assessed the extent of SARS-CoV-2 transmission in French Guiana conducting an intra-household transmission study and population-based seroprevalence surveys repeated over time. Methods: Household monitoring included virological and clinical follow-up for all household members for the first 28 days after the date of confirmation of the index case and serological follow-up over a 12-month period. Three seroprevalence surveys were conducted in July and September 2020 and in September 2021. Findings: A total of 57 dwellings including 245 individuals were included in the intra-household study. The average time between the date of onset of symptoms and the date of confirmation of diagnosis and inclusion in the study was 4.2 days and 7.2 days respectively. Secondary transmission was found in three quarters of households with a secondary infection rate of 35%. The highest transmission rate were observed in the most disadvantaged populations, within couples and from adults to children. Population-based seroprevalence studies have made it possible to monitor seroprevalence rates, which have varied from 15% at the time of the epidemic peak of the first epidemic wave to 65% of the population at the beginning of the fourth wave, despite the low impact of vaccination in French Guiana. Conclusion: The results obtained highlighted a high transmission of the virus in French Guiana associated with a low severity rate linked to the structure of the particularly young population. The project has provided health authorities with useful data to support prevention and control strategies and has allowed to evaluate the impact of interventions implemented during the pandemic.

Molecular multiplex assays (MPAs) for simultaneous detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza and respiratory syncytial virus (RSV) in a single RT-PCR reaction reduce time and increase efficiency to identify multiple pathogens with overlapping clinical presentation but different treatments or public health implications. Clinical performance of XpertXpress® SARS-CoV-2/Flu/RSV (Cepheid, GX), TaqPath™ COVID−19, FluA/B, RSV Combo kit (Thermo Fisher Scientific, TP), and PowerChek™ SARS-CoV-2/Influenza A&B/RSV Multiplex RT-PCR kit II (KogeneBiotech, PC) was compared to individual Standards of Care (SoC). Thirteen isolates of SARS-CoV-2, human seasonal influenza, and avian influenza served to assess limit of detection (LoD). Then, positive and negative residual nasopharyngeal specimens, collected under public health surveillance and pandemic response served for evaluation. Subsequently, comparison of effectiveness was assessed. The three MPAs confidently detect all lineages of SARS-CoV-2 and influenza viruses. MPA-LoDs vary from 1 to 2 Log10 differences from SoC depending on assay and strain. Clinical evaluation resulted in overall agreement between 97 and 100%, demonstrating a high accuracy to detect all targets. Existing differences in costs, testing burden and implementation constraints influence the choice in primary or community settings. TP, PC and GX, reliably detect SARS-CoV-2, influenza and RSV simultaneously, with reduced time-to-results and simplified workflows. MPAs have the potential to enhance diagnostics, surveillance system, and epidemic response to drive policy on prevention and control of viral respiratory infections.

This work identifies the protein “macrophage infectivity potentiator” of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth.

Coronavirus disease 19 (COVID-19) is the clinical manifestation of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection. A hallmark of COVID-19 is a lung inflammation characterized by an abundant leukocyte infiltrate, elevated levels of cytokines/chemokines, lipid mediators of inflammation (LMI) and microthrombotic events. Animal models are useful for understanding the pathophysiological events leading to COVID-19. One such animal model is the K18-ACE2 transgenic mice. Despite their importance in inflammation, the study of LMI in lung of SARS-CoV-2 infected K18-ACE2 mice has yet to be studied to our knowledge. Using tandem mass spectrometry, the lung lipidome at different time points of infection was analyzed. Significantly increased LMI included N-oleoyl-serine, N-linoleoyl-glycine, N-oleoyl-alanine, 1/2-linoleoyl-glycerol, 1/2-docosahexaenoyl-glycerol and 12-hydroxy-eicosapenatenoic acid. The levels of prostaglandin (PG) E1, PGF2α, stearoyl-ethanolamide and linoleoyl-ethanolamide were found to be significantly reduced relative to mock-infected mice. Other LMI were present at similar levels (or undetected) in both uninfected and infected mouse lungs. In parallel to LMI measures, transcriptomic and cytokine/chemokine profiling were performed. Viral replication was robust with maximal lung viral loads detected on days 2-3 post-infection. Lung histology revealed leukocyte infiltration starting on day 3 post-infection, which correlated with the presence of high concentrations of several chemokines/cytokines. At early times post-infection, the plasma of infected mice contained highly elevated concentration of D-dimers suggestive of blood clot formation/dissolution. In support, the presence of blood clots in the lung vasculature was observed during infection. RNA-Seq analysis of lung tissues indicate that SARS-CoV-2 infection results in the progressive modulation of several hundred genes, including several inflammatory mediators and genes related to the interferons. Analysis of the lung lipidome indicated modest, yet significant modulation of a minority of lipids. In summary, our study suggests that SARS-CoV-2 infection in humans and mice share common features, such as elevated levels of chemokines in lungs, leukocyte infiltration and increased levels of circulating D-dimers. However, the K18-ACE2 mouse model highlight major differences in terms of LMI being produced in response to SARS-CoV-2 infection. The potential reasons and impact of these differences on the pathology and therapeutic strategies to be employed to treat severe COVID-19 are discussed.

ABSTRACT Backyard farming with limited biosecurity creates a massive potential for zoonotic spillover. Cambodia, a developing nation in Southeast Asia, is a hub for emerging and endemic infectious diseases. Due to pandemic-induced job losses in the tourism sector, rumors suggest that many former Cambodian tour guides have turned to backyard farming as a source of income and food security. A cross-sectional study including 331 tour guides and 69 poultry farmers in Cambodia before and during the novel coronavirus disease 2019 (COVID-19) pandemic was conducted. Participants were administered a survey to assess food security, income, and general farming practices. Survey data were collected to evaluate the risk perceptions for avian influenza virus (AIV), antimicrobial resistance (AMR), and general biosecurity management implemented on these poultry farms. Overall, food security decreased for 80.1% of the tour guides during the COVID-19 pandemic. Approximately 21% of the tour guides interviewed used backyard poultry farming to supplement losses of income and food insecurity during the COVID-19 pandemic, with a significantly higher risk than for traditional poultry farmers. Agricultural intensification in Cambodia due to the COVID-19 pandemic has caused an influx of makeshift farms with limited biosecurity. Inadequate biosecurity measures in animal farms can facilitate spillover and contribute to future pandemics. Improved biosecurity and robust viral surveillance systems are critical for reducing the risk of spillover from backyard farms. IMPORTANCE While this study highlights COVID-19-associated changes in poultry production at a small scale in Cambodia, poultry production is expected to expand due to an increase in the global demand for poultry protein during the pandemic, changes in urbanization, and the reduction of the global pork supply caused by African swine fever (ASF). The global demand and surge in poultry products, combined with inadequate biosecurity methods, can lead to an increased risk of domestic animal and human spillovers of zoonotic pathogens such as avian influenza. Countries in regions of endemicity are often plagued by complex emergency situations (i.e., food insecurity and economic fallouts) that hinder efforts to effectively address the emergence (or reemergence) of zoonotic diseases. Thus, novel surveillance strategies for endemic and emerging infectious diseases require robust surveillance systems and biosecurity training programs to prevent future global pandemics.

Gut microbiota plays a role in the neonatal immune education and could influence susceptibility to Th2-type immune disorders, such as allergies, the most prevalent chronic diseases in early childhood. We studied the impact of oral Lactobacillus rhamnosus (L.rhamnosus) supplementation to pregnant/breastfeeding C57BL/6 mice on the development of allergic airways disease in their offspring. We observed that mice, from L.rhamnosus-treated mothers, inoculated with ovalbumin (OVA)-Aluminium hydroxide (ALUM) at 3 days of life and challenged intranasally 4 weeks later showed decreased Th2-associated cytokines, IgE and IgG1, lung eosinophilia and airway hyper-reactivity compared to OVA-sensitized mice from untreated mothers. In that setting, the L.rhamnosus treatment increased the number and maturation of splenic neonatal type 1 conventional dendritic cells (cDC1) that remained largely dominant over the cDC2 and favored their OVA-specific Th1 differentiation. In response to inhaled house dust mite (HDM) allergen, the maternal L.rhamnosus supplementation increased the number of neonatal pulmonary cDC1 expressing lower amount of costimulatory molecules compared with no supplementation and decreased the number of cDC2 without affecting their costimulatory molecules expression. An HDM-specific Foxp3+RORγt+ Treg polarization was monitored in the lung draining lymph nodes. Finally, we confirmed the inhibitory effect of maternal L.rhamnosus treatment on all the measured features of the HDM allergic airways reaction in their offspring. We conclude that maternal L.rhamnosus administration prevents Th2-type allergic airways disease in their neonates by favoring splenic cDC1/Th1 responses against ALUM-adjuvanted OVA or by promoting a pulmonary Foxp3+RORγt+ Treg activation against inhaled HDM.

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin’s lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs’ derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E3 (PGE3), 12-hydroxyeicosapentaenoic acid (12-HEPE) and N-eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state.

We address artisanal and small-scale gold mining in Peru. Using the data collected through field visits, we develop a System Dynamics (SD) model to examine the current operations of the gold supply chain, and its interplay with mercury and gas suppliers. The current mining operations cause potential health and environmental issues, due to high mercury usage, and other issues (e.g., safety issues). As a potential solution to overcome such problems, we consider incorporating a cyanide processing facility into the SD model, where we examine the amount of ore that a miner would be willing to sell to the facility under several payback scenarios. We formulate a mixed-integer programming model that prescribes the optimal transition plan of a miner from local production to selling their ore to the facility within a time horizon that maximizes a miner's profit. The optimal solution provides a 22% improvement in the miners' profit over that of their current operations. We also conduct a sensitivity analysis to test the sensitivity of the optimal solution to the changes in several input parameters. We discuss that the solution is most sensitive to the gold price changes and the least sensitive to the local production cost changes. [ABSTRACT FROM AUTHOR]