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Tomasz Gaszynski,1 Pavel Michalek,2 Pawel Ratajczyk1 1Department of Anaesthesiology and Intensive Therapy, Medical University of Lodz, Lodz, Poland; 2Department of Anaesthesia and Intensive Medicine, Charles University and General University Hospital, Prague, Czech RepublicCorrespondence: Tomasz Gaszynski, Department of Anaesthesiology and Intensive Therapy, Medical University of Lodz, Lodz, Poland, Email tomasz.gaszynski@umed.lodz.plBackground: The visualization of the glottis may be inadequate in morbidly obese patients when a standard Macintosh blade laryngoscope (MCL) is used. The Vie Scope® (VS) is a novel type laryngoscope consisting of a straight, enclosed, illuminated tube that offers intubation via a bougie using the paraglossal technique. In this prospective, nonrandomized comparative study, we tested the research hypothesis that the VS may improve visualization of the glottic larynx in comparison to the MCL.Materials and Methods: After obtaining institutional ethics committee approval, 60 morbidly obese patients (BMI > 40 kg/m2) undergoing elective non-head and neck surgery were included in the study. After induction of general anesthesia (GA), the glottic visualization was performed using the two laryngoscopes in succession, first MCL size 3 or 4 followed by the VS and was assessed using the modified Cormack–Lehane scale. Tracheal intubation was performed using the VS The first pass intubation success and the total success rate was recorded only for the VS Intubation time was not measured because of the paired study design.Results and Discussion: Mean demographic data included: age 41.9± 8.2 years, height 171.2± 10.2 cm, weight 129.9± 21.6 kg, BMI 44.95± 3.85 kg/m2. Using MCL, Cormack–Lehane grade 1 was observed in 36 (60%) cases; grade 2 in 7/60 (11.6%); grade 3 in 13/60 (21.7%); and grade 4 in 4/60 (6.7%). Poor laryngeal views represented by grades 3 and 4 were observed in 28.4% of patients with the MCL. Grades obtained with the VS were all grade 1 (100%). The first attempt intubation success was in 58/60 (96.7%) with the VS. No complications were observed.Conclusion: The Vie Scope® laryngoscope, using the paraglossal technique of tracheal intubation, significantly improves visualization of the vocal cords in morbidly obese patients compared to the standard Macintosh laryngoscope.Keywords: morbid obesity, intubation, Vie Scope® laryngoscope, direct laryngoscopy, Macintosh, difficult airway

Hana Stepankova,1,2 Marcin Swiatkowski,3 Rafal Kruszynski,3 Pavel Svec,1 Hana Michalkova,1 Vendula Smolikova,1,2 Andrea Ridoskova,1,4 Zbynek Splichal,1,2 Petr Michalek,1,2 Lukas Richtera,1,2 Pavel Kopel,5 Vojtech Adam,1,2 Zbynek Heger,1,2 Simona Rex1,2 1Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czechia; 2Central European Institute of Technology, Brno University of Technology, Brno, Czechia; 3Institute of General and Ecological Chemistry, Lodz University of Technology, Lodz, Poland; 4Central European Institute of Technology, Mendel University in Brno, Brno, Czechia; 5Department of Inorganic Chemistry, Faculty of Science, Palacky University, Olomouc, CzechiaCorrespondence: Simona RexDepartment of Chemistry and Biochemistry, Mendel University in Brno, Brno, CzechiaTel +420-5-4513-3350Fax +425-5-4521-2044Email simona.rex@mendelu.czPurpose: The present study deals with the in vitro evaluation of the potential use of coordination compound-based zinc oxide (ZnO) nanoparticles (NPs) for the treatment of triple negative breast cancer cells (TNBrCa). As BrCa is one of the most prevalent cancer types and TNBrCa treatment is difficult due to poor prognosis and a high metastasis rate, finding a more reliable treatment option should be of the utmost interest.Methods: Prepared by reacting zinc carboxylates (formate, acetate, propionate, butyrate, isobutyrate, valerate) and hexamethylenetetramine, 4 distinct coordination compounds were further subjected to two modes of conversion into ZnO NPs – ultrasonication with oleic acid or heating of pure precursors in an air atmosphere. After detailed characterization, the resulting ZnO NPs were subjected to in vitro testing of cytotoxicity toward TNBrCa and normal breast epithelial cells. Further, their biocompatibility was evaluated.Results: The resulting ZnO NPs provide distinct morphological features, size, biocompatibility, and selective cytotoxicity toward TNBrCa cells. They internalize into two types of TNBrCa cells and imbalance their redox homeostasis, influencing their metabolism, morphology, and ultimately leading to their death via apoptosis or necrosis.Conclusion: The crucial properties of ZnO NPs seem to be their morphology, size, and zinc content. The ZnO NPs with the most preferential values of all three properties show great promise for a future potential use in the therapy of TNBrCa.Keywords: carboxylate, hexamethylenetetramine, nanoparticles, redox homeostasis imbalance, triple negative breast cancer, zinc oxide coordination compounds

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1+ ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1+ ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).

Refugee children often face disruptions to their education before and during displacement. However, little is known about either levels or predictors of refugee children's literacy or about their attitudes toward reading in low- or middle-income countries. To address this, we conducted in-home literacy assessments using the Holistic Assessment of Learning and Development Outcomes with 322 Syrian refugee mother-child dyads who lived in Jordan (child age range 4-8 years, M = 6.32 years, 50% female). Overall, the children had quite low levels of literacy, although they indicated a strong enthusiasm for reading. Child age, maternal education, and maternal ability to read all predicted child literacy, although maternal literacy predicted it only among children enrolled in school. Among those enrolled in school (64.9% of the total sample, 88.7% of those aged [greater than or equal to] 6), students attending hybrid classes had better literacy than those attending either solely in-person or solely online, although the frequency of school attendance did not predict literacy. A less consistent pattern emerged for predicting children's attitudes toward reading. Our results suggest an urgent need to improve literacy skills among refugee children in Jordan, as well as a need for validated measures of attitudes toward reading for use with Arabic-speaking youth.

Sepsis is one of the most common causes of death in patients admitted to intensive care units (ICUs). The development of sepsis is significantly influenced by genetic predisposition. In this study, we highlight a potential association between a variant of the fat mass and obesity-associated (FTO) gene and risk of sepsis in children and adolescents.

An additively manufactured (nominally equiatomic) CrCoNi alloy was processed by laser powder bed fusion (LPBF). At ambient temperatures (298 K), this medium-entropy alloy displayed a yield strength, σy of ∼691 ± 9 MPa, and an ultimate tensile strength, σu of ∼926 ± 15.2 MPa; at cryogenic temperatures (77 K), yield and tensile strengths increased respectively to σy ∼ 944 ± 6 MPa and σu ∼ 1382 ± 11 MPa. These strength levels are 57 and 44% higher than that of the wrought alloy, due to strengthening from the solidification cellular structures intertwined with dislocations in the LPBF CrCoNi. The crack-initiation fracture toughness, KJIc was measured to be ∼183.7 ± 28 MPa√m at 298 K; this value marginally decreased by ∼4% to ∼176 ± 11 MPa√m at 77 K. These KJIc values of the LPBF CrCoNi were 11% and 35% lower than the wrought CrCoNi alloy at 298 K and 77 K, respectively. The resistance to crack growth of the LPBF CrCoNi from its hierarchical micro- and meso‑structures was evaluated using nonlinear-elastic fracture mechanics by measuring R-curve behavior in the form of the J-integral as a function of crack extension. The specific features of the hierarchical microstructures at different length-scales provide a basis for the strengthening and toughening properties of this additively manufactured medium-entropy alloy. This correlation between the deformation and the hierarchical microstructures at different length-scales may provide future guidance for improving the fracture toughness properties of medium-entropy alloys.

Abstract High-fidelity patterning of thin metal films on arbitrary soft substrates promises integrated circuits and devices that can significantly augment the morphological functionalities of freeform electronics. However, existing patterning methods that decisively rely on prefabricated rigid masks are severely incompatible with myriad surfaces. Here, we report printable, stretchable metal-vapor-desorption layers (s-MVDLs) that can enable high-fidelity patterning of thin metal films on freeform polymeric surfaces. The printed rubbery matrix with highly mobile chains effectively repels various metal vapors from the surface and inhibits their condensation, thereby allowing selective metal deposition. The s-MVDLs are printed by direct ink writing techniques, enabling customizable and scalable thin metal patterns ranging from the micrometer to millimeter scale with high fidelity. Furthermore, the superior stretchability and mechanical robustness of the s-MVDLs allow highly compliant deformation along the substrates, enabling the construction of unconventional circuits and devices on multi-curvature, non-developable, and stretchable surfaces.

Abstract Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1 + ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1 + ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).

Abstract Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .

Abstract Community-led, shared book reading programs may help improve refugee children’s reading abilities and attitudes towards reading. We Love Reading (WLR)—a light-touch, community-led, shared book reading program—was evaluated in a pre-registered, wait-listed, randomised controlled trial (AEARCTR-0006523). 322 Syrian refugee mother–child dyads (children: 4–8-year-olds, 50.0% female) in Jordan were tested at two timepoints, 15 weeks apart. WLR did not significantly affect child literacy or child-reported child attitudes toward reading (ps > 0.05). Mothers did report improved child attitudes toward reading from WLR (p = 0.046, η 2 = 0.013). The intervention did not lead to improvements in family relationships (ps > 0.05). WLR may have promise in improving attitudes toward reading in forcibly displaced children but did not affect literacy or child-reported attitudes toward reading; these results provide insight into what changes are needed for effective shared book reading interventions in this population.

Introduction: While ample data demonstrate the effectiveness of inpatient psychosomatic treatment, clinical observation and empirical evidence demonstrate that not all patients benefit equally from established therapeutic methods. Especially patients with a comorbid personality disorder often show reduced therapeutic success compared to other patient groups. Due to the heterogeneous and categorical personality assessment, previous studies indicated no uniform direction of this influence. This complicates the derivation of therapeutic recommendations for mental disorders with comorbid personality pathology. Methods: Analyzing n = 2094 patients from German university hospitals enrolled in the prospective “MEPP” study, we tested the dynamic interaction between dimensionally assessed personality functioning and psychopathology of anxiety and depression. Results: Longitudinal structural equation modelling replicated the finding that the severity of symptoms at admission predicts symptom improvement within the same symptom domain. In addition, we here report a significant coupling parameter between the baseline level of personality function and the change in general psychopathology - and vice versa. Discussion and conclusion: These results imply that personality pathology at admission hinders the therapeutic improvement in anxiety and depression, and that improvement of personality pathology is hindered by general psychopathology. Furthermore, the covariance between both domains supports the assumption that personality functioning and general psychopathology cannot be clearly distinguished and adversely influence each other. A dimensional assessment of the personality pathology is therefore recommendable for psychotherapy research and targeted therapeutic treatment.

Seaweed aquaculture is gaining traction globally as a solution to many climate issues. However, seaweeds themselves are also under threat of anthropogenically driven climate change. Here, we summarize climate-related challenges to the seaweed aquaculture industry, with a focus on the developing trade in the North Atlantic. Specifically, we summarize three main challenges: i) abiotic change; ii) extreme events; and iii) disease & herbivory. Abiotic change includes negative effects of ocean warming and acidification, as well as altered seasonality due to ocean warming. This can lower biomass yield and change biochemical composition of the seaweeds. Extreme events can cause considerable damage and loss to seaweed farms, particularly due to marine heatwaves, storms and freshwater inputs. Seaweed diseases have a higher chance of proliferating under environmentally stressful conditions such as ocean warming and decreased salinity. Herbivory causes loss of biomass but is not well researched in relation to seaweed aquaculture in the North Atlantic. Despite challenges, opportunities exist to improve resilience to climate change, summarized in three sections: i) future proof site selection; ii) advances in breeding and microbiome manipulation; and iii) restorative aquaculture. We present a case study where we use predictive modelling to illustrate suitable habitat for seaweed cultivation in the North Atlantic under future ocean warming. Notably, there was a large loss of suitable habitat for cultivating Alaria esculenta and Laminaria digitata. We show how selection and priming and microbe inoculates may be a cost-effective and scalable solution to improve disease- and thermal tolerance. Co-cultivation of seaweeds may increase both yield and biodiversity co-benefits. Finally, we show that aquaculture and restoration can benefit from collaborating on nursery techniques and push for improved legislation.

Abstract Introduction The annulus fibrosus (AF) of the Intervertebral disc (IVD) is composed of concentric lamellae of helically wound collagen fibers. Understanding the spatial variation of collagen fiber orientations in these lamellae, and the resulting material anisotropy, is crucial to predicting the mechanical behavior of the complete IVD. Methods This study builds on a prior model predicated on path‐independent displacement of fiber endpoints during vertebral body growth to predict a complete, three‐dimensional annulus fibrosus fiber network from a small number of subject‐independent input parameters and vertebral endplate topographies obtained from clinical imaging. To evaluate the model, it was first fit to mid‐plane fiber orientations obtained using polarized light microscopy in a population of bovine caudal discs for which computed tomography images vertebral endplates were also available. Additionally, the model was used to predict the trajectories based on human lumbar disc geometries and results were compared to previously reported data. Finally, the model was employed to investigate potential disc‐related variations in fiber angle distributions. Results The model was able to accurately predict experimentally measured fiber distributions in both bovine and human discs using only endplate topography and three input parameters. Critically, the model recapitulated previously observed asymmetry between the inclinations of right‐ and left‐handed fibers in the posterolateral aspect of the human AF. Level to level variation of disc height and aspect ratio in the human lumbar spine was predicted to affect absolute values of fiber inclination, but not this asymmetry. Conclusion Taken together these results suggest that patient‐specific distributions of AF fiber orientation may be readily incorporated into computational models of the spine using only disc geometry and a small number of subject‐independent parameters.

The design specifications of composite trusses are only partially included in the European standards. However this construction system can be considered as one of the most economical for building and bridge structures. To create an interaction between steel and concrete, it is necessary to prevent the relative slip at the steel and concrete interface using the shear connectors. But the local effects of a concentrated longitudinal shear force between steel truss chord and concrete slab, as special task, should be appropriately examined. The finite element analyses can be used to investigate numerically this structural system behaviour, exploiting several computer procedures. The experimental research has tested these procedures. The outputs of this study are presented in the paper.

Abstract All-polymer solar cells (all-PSCs) offer improved morphological and mechanical stability compared with those containing small-molecule-acceptors (SMAs). They can be processed with a broader range of conditions, making them desirable for printing techniques. In this study, we report a high-performance polymer acceptor design based on bithiazole linker (PY-BTz) that are on par with SMAs. We demonstrate that bithiazole induces a more coplanar and ordered conformation compared to bithiophene due to the synergistic effect of non-covalent backbone planarization and reduced steric encumbrances. As a result, PY-BTz shows a significantly higher efficiency of 16.4% in comparison to the polymer acceptors based on commonly used thiophene-based linkers (i.e., PY-2T, 9.8%). Detailed analyses reveal that this improvement is associated with enhanced conjugation along the backbone and closer interchain π-stacking, resulting in higher charge mobilities, suppressed charge recombination, and reduced energetic disorder. Remarkably, an efficiency of 14.7% is realized for all-PSCs that are solution-sheared in ambient conditions, which is among the highest for devices prepared under conditions relevant to scalable printing techniques. This work uncovers a strategy for promoting backbone conjugation and planarization in emerging polymer acceptors that can lead to superior all-PSCs.

Abstract We examine the relationship between electric vehicle battery chemistry and supply chain disruption vulnerability for four critical minerals: lithium, cobalt, nickel, and manganese. We compare the nickel manganese cobalt (NMC) and lithium iron phosphate (LFP) cathode chemistries by (1) mapping the supply chains for these four materials, (2) calculating a vulnerability index for each cathode chemistry for various focal countries and (3) using network flow optimization to bound uncertainties. World supply is currently vulnerable to disruptions in China for both chemistries: 80% [71% to 100%] of NMC cathodes and 92% [90% to 93%] of LFP cathodes include minerals that pass through China. NMC has additional risks due to concentrations of nickel, cobalt, and manganese in other countries. The combined vulnerability of multiple supply chain stages is substantially larger than at individual steps alone. Our results suggest that reducing risk requires addressing vulnerabilities across the entire battery supply chain.

We conduct a discrete choice experiment across 771 U.S. households to estimate willingness to pay (WTP) values for autonomous and human grocery delivery. We estimate that urban households, on average, are willing to pay about $6.70 for same-day human delivery to the household’s doorstep. This value drops by about $1.90 for autonomous delivery, by $2.30 per day of delivery delay, and by $3.10 or $7.90 for delivery to curbside or neighborhood locker locations, respectively. Households located 20 min or more from the nearest major grocery store are willing to pay $3 more for delivery than other households and are more willing to accept delivery delay and curbside or locker delivery locations, while households below the poverty line are less sensitive to delivery delay. Using a latent class logit model, we identify three distinct types of consumers: (1) Delivery Compromisers, representing 45% of weighted respondents, prefer delivery but are sensitive to timing, location, and automation; (2) Delivery Indifferent consumers (39%) have no statistically significant WTP for delivery over in-person shopping; and (3) Delivery Enthusiasts (16%) have high WTP for delivery. Simulation results suggest that if autonomous delivery were able to provide rapid delivery at low cost, it could potentially capture a majority of shopping choices for the Enthusiast groups and a substantial share of choices for Compromisers.

Abstract Understanding changes in the hazard component of climate risk is important to inform societal resilience planning in a changing climate. Here, we examine local changes in wind speed, rainfall, and flooding related to tropical cyclones (TCs) and compare them across statistical and dynamical modeling approaches. Our focus region is the Delaware River Basin, located in the northeastern United States. We pair event‐based downscaling with large ensemble climate model information to capture the details of extreme TC wind, rain, and flooding, and their likelihood, in a changing climate. We identify local TCs in the Community Earth System Model 2 Large Ensemble (CESM2‐LENS). We find fewer TCs in the future, but these future storms have higher wind speeds and are wetter. We also find that TCs produce heavier 3‐day precipitation distributions than all other summertime weather events, with TCs constituting a larger percentage of the upper tail of the full precipitation distribution. With this information, we identify a small collection of 200‐year return events and compare the resulting TC rain and wind across dynamical and statistical downscaling methods. We find that dynamical downscaling produces peak rain rates far higher than CESM or the statistical downscaling method. It can also produce quite different future changes in precipitation totals for the small set of events considered here. This leads to vastly different flood responses. Overall, our results highlight the need to interpret future changes of event‐based simulations in the context of downscaling method limitations.

Summary: It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.