CD19-directed chimeric antigen receptor T lymphocytes (CAR-T) have led to durable remissions in children with refractory and/or multiply relapsed B-lymphoblastic leukemia. For those who relapse or lose B-cell aplasia post-CAR-T, the role of CAR-T reinfusion is unclear. We report a case of durable remission with tisagenlecleucel reinfusion despite failure to achieve B-cell aplasia and compare this case to seven additional children who received multiple tisagenlecleucel infusions at our institution. Our experience suggests that reinfusion is safe and may be a definitive therapy for a small subset of patients. Reinfusion can also reintroduce remission and/or B-cell aplasia, allowing for subsequent therapies.

The therapeutic effects of human mesenchymal stromal cells (MSC) have been attributed mostly to their paracrine activity, exerted through small-secreted extracellular vesicles (EVs) rather than their engraftment into injured tissues. Currently, the production of MSC-derived EVs (MSC-EVs) is performed in laborious static culture systems with limited manufacturing capacity using serum-containing media. In this work, a serum-/xenogeneic-free microcarrier-based culture system was successfully established for bone marrow-derived MSC cultivation and MSC-EV production using a 2 L-scale controlled stirred tank reactor (STR) operated under fed-batch (FB) or fed-batch combined with continuous perfusion (FB/CP). Overall, maximal cell numbers of (3.0±0.12)×10 8 and (5.3±0.32)×10 8 were attained at days 8 and 12 for FB and FB/CP cultures, respectively, and MSC(M) expanded under both conditions retained their immunophenotype. MSC-EVs were identified in the conditioned medium collected from all STR cultures by TEM, and EV protein markers were successfully identified by WB analysis. Overall, no significant differences were observed between EVs isolated from MSC expanded in STR operated under the two feeding approaches. EV mean sizes of 163±5.27 nm and 162±4.44 nm (P>0.05) and concentrations of (2.4±0.35)x10 11 EVs/mL and (3.0±0.48)x10 11 EVs/mL (P>0.05) were estimated by nanoparticle tracking analysis for FB and FB/CP cultures, respectively. The STR-based platform optimized herein represents a major contribution towards the development of human MSC- and MSC-EV-based products as promising therapeutic agents for Regenerative Medicine settings.

Abstract Objective To compare the gestational age of neonates in utero exposed to benzodiazepines (BDZs) with none exposed controls. Secondary objectives were; birth weight, presence of congenital malformations, APGAR score, and the need for > 3 months (prolonged) maternal psychiatric care. Study design A retrospective cohort study of women and neonates from 2013 to 2021 with univariate and multivariable analysis to study the associations between BDZs exposure and gestational age compared to non-exposed women with mental health problems. Results We found that BDZ exposure was associated with a lower gestational age of -3.2 days (95% CI -5.8 , -0.53 days). Women in the exposed group had an increased risk of psychiatric care (adjusted OR 2.511 (95% CI 1.675 – 3.782), p < 0.001). Conclusion We found that in utero BDZ exposure was independently associated with a significantly lower gestational age of the neonates and prolonged psychiatric care of their mothers.

Despite of superior performance of the oxide-derived copper (OD-Cu) in producing valuable hydrocarbons during CO2RR, its fabrication process is still ambiguous and complicated. In this work, we develop a simple microwave-assisted method to synthesize the oxide-derived Cu nanosheet (OD-Cu NS) and reveal that the oxidation state of Cu species is controlled by varying the Cu precursor amount. Notably, the simultaneous formation of nano-sized Cu domains influence the surface roughness of OD-Cu NS. The partially oxidized Cu surface exhibits a superior faradaic efficiency (FE) of C2+ products up to 72%, along with a partial current density of 55 mA cm−2 in a neutral KHCO3 solution. More importantly, the as-obtained OD-Cu NS shows a synergetic effect on dissociating of CO2 molecules by the strong binding energy and promoting of C2+ compounds productivity by the enlarged electrochemical surface area. This work provides a new insight for designing efficient OD-Cu catalysts towards CO2RR.

Some transformations acting on radially symmetric solutions to the following class of non-homogeneous reaction-diffusion equations | x | σ 1 ∂ t u = ∆ u m + | x | σ 2 u p , ( x , t ) ∈ R N × ( 0 , ∞ ) , which has been proposed in a number of previous mathematical works as well as in several physical models, are introduced. We consider here m≥1, p≥1, N≥1 and σ 1 , σ 2 real exponents. We apply these transformations in connection to previous results on the one hand to deduce general qualitative properties of radially symmetric solutions and on the other hand to construct self-similar solutions which are expected to be patterns for the dynamics of the equations, strongly improving the existing theory. We also introduce mappings between solutions which work in the semilinear case m=1.

To date no single gas chromatographic method can simultaneously measure all fatty acids (FA), including trans FA (TFA), that are contained in dairy products, partially hydrogenated oils (PHO), and refined vegetable oils. Using 100% poly(biscyanopropyl siloxane) capillary columns, ruminant and dairy fats are preferentially analyzed by applying temperature programs that separate short chain FA, but not trans-18:3 from 20:1. Refined vegetable oils and PHO are preferentially analyzed by applying isothermal elutions that provide quantification of all 18 carbon TFA including trans-18:3 FA, but not of all short chain FA. In this short communication, we propose a temperature program method capable of simultaneously measuring short chain FA and all 18 carbon TFA including trans-18:3 by applying a negative temperature gradient after the elution of trans-18:1. A simplified version of the method is also described for equipment not able to perform negative temperature gradients.

In this study, the effects of solid-state fermentation (SSF), including strain (Aspergillus niger NRRL 334 and A. oryzae NRRL 5590) and fermentation time (24, 48, and 72 h) on the nutritional value of cold-pressed (CP) and hexane-extracted (HE) canola meals were examined. SSF increased the protein content of both types of meals (from ~36 to ~40%) while reducing the oil content of CP meals (from ~12 to 9%). There was a significant reduction (~80%) in the phytic acid content of both types of meals after fermentation using either fungi. Overall, fermented samples showed a decrease in the total phenolic content from 2.7-3.1 to ~1.0 mg gallic acid equivalents (GAE)/g DM (a ~65% reduction), of which specifically the HE meal fermented with A. niger sample had the greatest decrease from 3.1 to 0.6 mg GAE/g DM (~81% reduction). Seventy-two hours of fermentation decreased the in vitro protein digestibility (IVPD) of the meals. In contrast, a shorter fermentation time (24 h) increased the IVPD as compared to the controls (from ~73% to 77-81%), with the exception of the CP meal fermented with A. niger which had decreased IVPD at all fermentation times. Overall, the changes indicate that SSF using A. niger or A. oryzae can be useful to positively modify the composition of different canola meals and improve their nutritional value by significantly increasing the protein content, decreasing the levels of antinutrients, while only slightly reducing IVPD.

Septicemia can be a tragic illness in neonatal and young foals. Sick foals may manifest a variety of clinical symptoms all related to a common infection and its systemic effects. While the pathogenesis of this disease is the same as for adult equids, the clinical signs seen can be very different. The rapid changes seen in foal are reflective of their low endogenous reserves of glucose and innate immune mediators as well as the poor ability to self-regulate their metabolism. The neonatal immune system is reliant on maternal antibodies at birth and development of the foal's own system takes a significant amount of time. This non-competent immune system changes how the foal responds to infection when compared to the adult. Clinical signs in septic foals include tachycardia, tachypnea, depression, anorexia, colitis, and fever. Less commonly, foals may show petechiation, swollen joints, anterior uveitis, and coma. This article is the first of a two part series on neonatal sepsis and will present a review on the neonatal immune system, the pathophysiology of sepsis, and the range of clinical signs seen in foals.

The tendency to ruminate (i.e., repetitive, self-referential, negative thoughts) is a maladaptive form of emotional regulation and represents a transdiagnostic vulnerability factor for stress-related psychopathology. Vagally-mediated heart rate variability (HRV), reflecting parasympathetic nervous system activity, is commonly used as a physiological marker of stress regulation. Past research has suggested a link between trait rumination and resting HRV at baseline; however, inconsistent results exist in healthy individuals. In this study, we investigated the association between the tendency to ruminate and resting HRV measured at baseline in a healthy population using a large cross-sectional dataset (N = 1189, 88% women; mean age = 21.55, ranging from 17 to 48 years old), which was obtained by combining samples of healthy individuals from different studies from our laboratory. The results showed no cross-sectional correlation between resting baseline HRV and trait rumination (confirmed by Bayesian analyses), even after controlling for important confounders such as gender, age, and depressive symptoms. Also, a nonlinear relationship was rejected. In summary, based on our results in a large sample of healthy individuals, baseline resting HRV is not a trait marker of the tendency to ruminate.

Permafrost regions are under particular pressure from climate change resulting in widespread landscape changes, which impact also freshwater chemistry. We investigated a snapshot of hydrochemistry in various freshwater environments in the lower Kolyma river basin (North-East Siberia, continuous permafrost zone) to explore the mobility of metals, metalloids and non-metals resulting from permafrost thaw. Particular attention was focused on heavy metals as contaminants potentially released from the secondary source in the permafrozen Yedoma complex. Permafrost creeks represented the Mg-Ca-Na-HCO 3-Cl-SO 4 ionic water type (with mineralisation in the range 600-800 mg/L), while permafrost ice and thermokarst lake waters were the HCO 3-Ca-Mg type. Multiple heavy metals (As, Cu, Co, Mn and Ni) showed much higher dissolved phase concentrations in permafrost creeks and ice than in Kolyma and its tributaries, and only in the permafrost samples and one Kolyma tributary have we detected dissolved Ti or Hg. In thermokarst lakes, several metal and metalloid dissolved concentrations increased with water depth (Fe, Mn, Ni and Zn - in both lakes; Al, Cu, K, Sb, Sr and Pb in either lake), reaching 1370 µg/L Cu, 4610 µg/L Mn, and 687 µg/L Zn in the bottom water layers. Permafrost-related waters were also enriched in dissolved phosphorus (up to 512 µg/L in Yedoma-fed creeks). The impact of permafrost thaw on river and lake water chemistry is a complex problem which needs to be considered both in the context of legacy permafrost shrinkage and the interference of the deepening active layer with newly deposited anthropogenic contaminants.

Objective: To investigate post-intubation laryngeal complications in severe COVID-19 patients. Methods: From September 2020 to April 2021, consecutive patients presenting with laryngological symptoms following severe COVID-19 infection and related intubation were included. Demographic, age, gender, comorbidities, symptoms, intubation duration, tracheostomy features, and laryngeal findings were collected. Videolaryngostroboscopy findings were analyzed by two senior laryngologists in a blind manner. Results: Forty-three patients completed the evaluations. The intubation duration was <14 days in 22 patients (group 1) and >14 days in 21 patients (group 2). The following abnormalities were found on an average post-intubation time of 51.6 days: posterior glottic stenosis (N=14), posterior commissure hypertrophy (N=19) or laryngeal diffuse edema (N=10), granuloma (N=8), laryngeal necrosis (N=2), vocal fold atrophy (N=2), subglottic stenosis (N=1) and glottic flange (N=1). Sixteen patients required surgical treatment (N=17 procedures). The number of intubation days was significantly higher in patients with posterior glottic stenosis (26.1 ± 9.4) compared with those presenting posterior commissure hypertrophy (11.5 ± 2.9) or granuloma (15.1 ± 5.8; p<0.001). Fourteen patients required surgical management. Conclusion: Prolonged intubation used in severe COVID-19 patients is associated with significant laryngeal disorders. Patients with a history of >2-week intubation have a higher risk of posterior glottic stenosis.

Like many top consumers, parasites can regulate feeding of their prey via trait-mediated means. If parasites modify the feeding behavior of ecologically important grazers, they may have cascading effects on the structure and functioning of whole plant communities. The extent to which parasites can influence plant communities in this way is largely dependent on the strength of their behavioral alteration, their prevalence in host grazers, and the density of those hosts. Recent experiments and comparative surveys in southeastern USA salt marshes revealed that common larval trematode parasites suppress the per capita grazing impacts of the marsh periwinkle (Littoraria irrorata), generating a trophic cascade that protects foundational marsh plants from drought-associated overgrazing. Here, we conducted a field manipulation wherein we modified grazer host density while holding infection prevalence constant at an ecologically relevant level (20%) to determine whether the indirect, facilitative effects of parasites on marsh plants varied with the density of grazers. We found that parasites had significant positive impacts on marsh net primary productivity at moderate densities of snails (≥50 snails/ 0.5 m2), but that the positive effects of parasites were negligible at lower densities. Our results confirm the findings of previous studies that parasites can protect marsh plants from overgrazing at sufficiently high prevalence, but show that their ability to do so depends on host density.

BJOG-22-1117.R1: Are Kielland’s Forceps a Safe Option for Birth?Kielland’s rotational forceps deliveries often divide opinion, deriving reactions akin to Marmite, the notorious UK spread. Love or hate them, as many maternity professionals do, what does the current evidence say?The aim of the meta-analysis by Giacchino et al was to estimate the risk of maternal and neonatal complications following Kielland’s births more accurately, when compared with rotational ventouse, non-rotational forceps birth and second stage caesarean section. The authors included 13 observational studies, all published after 2000 to reflect current practice and reported meta-analyses using a random-effects model to allow for clinical heterogeneity.Unsurprisingly, the authors found that Kielland’s births had lower rate of post-partum haemorrhage and of a low 5-minute Apgar score compared to second-stage caesarean. When the cervix is fully dilated, a caesarean has been yet again shown not to be the best ‘way out’, except when it becomes the only ‘way out’ after a failed attempt at instrumental vaginal birth. They also found that babies born by Kielland’s had lower prevalence of significant trauma compared to rotational ventouse, similar to Al-Wattar et al (Curr Opin Obstet Gynaecol 2015;27(6):438-44). This is hardly surprising; despite their notoriety, Kielland’s in the hands of a trained experienced accoucheur can be applied to posterior and transverse malposition, prematurity, face presentation, and in the presence of significant caput. They can also be used for ‘asynclitic occipito-anterior’, a term which has crept into practice in the last couple of decades to describe an occiput more than 45 degrees from the midline where non-rotational forceps could not and should not be used. In observational studies in single centres with expertise, including the papers included in Giacchino et al, Kielland’s are highly effective.Which brings us to key issues not addressed in the review by Giacchino et al. Who is trained nowadays to use Kielland’s safely? And are they safe enough for women’s perineum? In a national UK audit (Tempest et al. Acta Obstet Gynecol Scand 2020;99:537-45) Kiellands were used less often than other methods, particularly for transverse occiput positions. When they were used, the rate of anal sphincter injury was higher with Kielland’s compared to manual rotation.ROTATE, a multicentre RCT in the UK, aims to address these issues with robust methods, and also examine other important outcomes including mental health and continence (https://fundingawards.nihr.ac.uk/award/NIHR127818). Concurrently, innovative research with nano-sensors (Jaufuraully et al, BJOG 2022;129:71) has the potential to make rotational birth techniques safer and more effective regardless of the method used.Such research may take a while before it produces findings applicable to clinical practice. In the meantime, it remains critical to train accoucheurs appropriately, for example with courses such as ROBUST and ART&CRAFT in the UK; but also to propagate good clinical practice beyond isolated silos, before obstetricians become completely deskilled globally. A possible solution would be for centres of excellence in rotational birth to offer apprenticeships to senior obstetricians from other maternity units. Training junior accoucheurs cannot translate into safer practice unless their mentors are also trained and confident to supervise them.

Background: Killer-cell immunoglobulin-like receptors 2DL4 ( KIR2DL4) and the human leukocyte antigen class I-G ( HLA-G) display vital parts in immune responses against HCV infection. We select four potentially functional SNPs of KIR/HLA to explore the associations between KIR2DL4/HLA-G genetic variants and HCV infection results. Methods: In the present case-control investigation, KIR2DL4-rs660773， KIR2DL4-rs660437， HLA-G-rs9380142, and HLA-G-rs1707 SNPs were sorted as genotype in a total of 2225 high-risk subjects, involving 1778 paid blood donors and 447 drug users. The SNPs were functionally annotated using bioinformatics analysis. Results: Following adjusting by age, sex, ALT, AST, IFNL4-rs12979860, IFNL4-rs8099917, and the infection route, the logistic regression analysis (LRA) discovered that KIR2DL4-rs660773 and HLA-G-rs9380142 were correlated with vulnerability to HCV infection (all P <0.05). In a locus-dosage way, compared with subjects carrying the rs9380142-AA or rs660773-AA genotypes, subjects with rs9380142-AG or rs660773-AG/GG (all P <0.05) were more vulnerable to HCV infection; the overall impact of their risk genotypes (rs9380142-AGrs660773-AG/GG) was correlated with an elevated incidence of HCV infection ( Ptrend<0.001). In the Haplotype analysis, patients with haplotype AG were more likely to contract HCV compared to those with the highest common AA haplotype ( P= 0.002) were higher in susceptibility to infect HCV.nThe SNPinfo web server estimated that rs660773 is a transcription factor binding site (TFBS), whereas rs9380142 is a potential microRNA-binding site. Conclusion: In the Chinese high-risk population, KIR2DL4 rs660773 and HLA-G rs9380142 polymorphisms are related to HCV susceptibility .

In the face of global biodiversity declines, surveys of beneficial and antagonistic arthropod diversity as well as the ecological services that they provide are increasingly important in both natural and agro-ecosystems. Conventional survey methods used to monitor these communities often require extensive taxonomic expertise and are time-intensive, potentially limiting their application in industries such as agriculture, where arthropods often play a critical role in productivity (e.g. pollinators, pests and predators). Environmental DNA (eDNA) metabarcoding of a novel substrate, crop flowers, may offer an accurate and high throughput alternative to aid in the detection managed and unmanaged arthropod taxa (e.g. flower-visiting insects and potential pollinators). Here, we compared the arthropod communities detected with eDNA metabarcoding of flowers, from an agricultural species (Persea americana - ‘Hass’ avocado), with two conventional survey techniques; Digital Video Recording (DVR) devices and pan traps. In total, 80 eDNA flower samples, 96 hours of DVRs and 48 pan trap samples were collected. Across the three methods, 49 arthropod families were identified, of which 12 were unique to the eDNA dataset. Alpha diversity levels did not differ across the three survey methods although taxonomic composition varied significantly, with only 12% of arthropod families found to be common across all three methods. This study demonstrates that eDNA metabarcoding of flowers to detect visiting arthropods, although in a developmental stage, can complement traditional survey methods and increase the diversity of taxa detected with implications for both natural and agro-ecosystems.

Genotype environment association (GEA) studies have the potential to identify the genetic basis of local adaptation in natural populations. Specifically, GEA approaches look for a correlation between allele frequencies and putatively selective features of the environment. Genetic markers with extreme evidence of correlation with the environment are presumed to be tagging the location of alleles that contribute to local adaptation. In this study, we propose a new method for GEA studies called the weighted-Z analysis (WZA) that combines information from closely linked sites into analysis windows in a way that was inspired by methods for calculating FST. We analyze simulations modelling local adaptation to heterogeneous environments to compare the WZA with existing methods. In the majority of cases we tested, the WZA either outperformed single-SNP based approaches or performed similarly. In particular, the WZA outperformed individual SNP approaches when a small number of individuals or demes was sampled. We apply the WZA to previously published data from lodgepole pine and identified candidate loci that were not found in the original study.

Influenza A infection can mimic coronavirus disease 2019 (COVID-19) in case of their signs and symptoms, making it almost impossible to distinguish them clinically, necessitating using high-precision assays in such patients. Clinicians should be careful in treating such patients merely based on their unspecific manifestations.

Ample evidence has indicated shifts in distribution of fish populations in response to environmental stress. However, most studies focused at the whole population scale. This neglects the spatial dynamics between groups of different body size (body size groups), that fundamentally shapes the spatial structure of a population. Here, we explored the mechanisms that modulate spatial dynamics of body size groups, and applied our analyses to three North Sea fish populations which experienced severe declines in biomass from 1977 to 2019: Atlantic cod (Gadus morhua), haddock (Melanogrammus aeglefinus), and whiting (Merlangius merlangius). All three populations exhibited strong declines in the overlapped area between body size groups in winter over 43 years, yet their mechanisms differed. These declines were either due to (1) different magnitudes of contraction of the distribution area of body size groups; and/or (2) different speeds and directions of spatial shift among various body size groups, both increasing spatial segregation within populations. These patterns were either associated with ocean warming, and/or declining population biomass, and such associations often varied according to distinct body size groups. Our analytical approach provides a powerful tool for identifying vulnerable populations under environmental stress and can be generalized to study a variety of size/age structured populations at various ecosystem types.