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As a nutrient rich emulsion extracted from plant materials, plant-based milk (PBM) has been the latest trend and hot topic in the food industry due to the growing awareness of consumers toward plant-based products in managing the environmental (carbon footprint and land utility), ethical (animal well-fare) and societal (health-conscious) issues. There have been extensive studies and reviews done to discuss the distinct perspective of PBM including its production, health effects and market acceptance. However, not much has been emphasized on the valuable antioxidants present in PBM which is one of the attributes making them stand apart from dairy milk. The amounts of antioxidants in PBM are important. They offered tremendous health benefits in maintaining optimum health and reducing the risk of various health disorders. Therefore, enhancing the extraction of antioxidants and preserving their activity during production and storage is important. However, there is a lack of a comprehensive review of how these antioxidants changes in response to different processing steps involved in PBM production. Presumably, antioxidants in PBM could be potentially lost due to thermal degradation, oxidation or leaching into processing water. Hence, this paper aims to fill the gaps by addressing an extensive review of how different production steps (germination, roasting, soaking, blanching, grinding and filtration, and microbial inactivation) affect the antioxidant content in PBM. In addition, the effect of different microbial inactivation treatments (thermal or non-thermal processing) on the alteration of antioxidant in PBM was also highlighted. This paper can provide useful insight for the industry that aims in selecting suitable processing steps to produce PBM products that carry with them a health declaration. [ABSTRACT FROM AUTHOR]

Objectives: To assess the short term temporal variations in suicide risk related to the day of the week and national holidays in multiple countries., Design: Multicountry, two stage, time series design., Setting: Data from 740 locations in 26 countries and territories, with overlapping periods between 1971 and 2019, collected from the Multi-city Multi-country Collaborative Research Network database., Participants: All suicides were registered in these locations during the study period (overall 1 701  286 cases)., Main Outcome Measures: Daily suicide mortality., Results: Mondays had peak suicide risk during weekdays (Monday-Friday) across all countries, with relative risks (reference: Wednesday) ranging from 1.02 (95% confidence interval (CI) 0.95 to 1.10) in Costa Rica to 1.17 (1.09 to 1.25) in Chile. Suicide risks were lowest on Saturdays or Sundays in many countries in North America, Asia, and Europe. However, the risk increased during weekends in South and Central American countries, Finland, and South Africa. Additionally, evidence suggested strong increases in suicide risk on New Year's day in most countries with relative risks ranging from 0.93 (95% CI 0.75 to 1.14) in Japan to 1.93 (1.31 to 2.85) in Chile, whereas the evidence on Christmas day was weak. Suicide risk was associated with a weak decrease on other national holidays, except for Central and South American countries, where the risk generally increased one or two days after these holidays., Conclusions: Suicide risk was highest on Mondays and increased on New Year's day in most countries. However, the risk of suicide on weekends and Christmas varied by country and territory. The results of this study can help to better understand the short term variations in suicide risks and define suicide prevention action plans and awareness campaigns., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at URL www.icmje.org/disclosure-of-interest/ and declare no support for the present study; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. This study did not include plans to recruit participants and only used pre-existing datasets. All data used in this study were pre-recorded and completely de-identified., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce., Methods: To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation., Results: We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis., Conclusions: This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.

Sulfur hexafluoride (SF 6 ) is widely used in the power industry and significantly contributes to the greenhouse effect, necessitating the development of efficient materials for SF 6 capture, particularly fluorine-containing materials. However, existing fluorine-containing materials often require complex monomers and high synthesis temperatures. Herein, we report the synthesis of a fluorine-functionalized carbazole-based nanoporous organic polymer (CNOP-7) at room temperature, using commercially available 4,4'-bis(9 H -carbazole-9-yl)-1,1'-biphenyl and 1,1,1-trifluoroacetone. CNOP-7 contains 14.7% fluorine atoms and exhibits a high specific surface area of 1270 m 2 ·g -1 , demonstrating excellent SF 6 adsorption and separation performance. The SF 6 /N 2 selectivity of CNOP-7 reaches 107 at 273 K and 73 at 298 K. Furthermore, dynamic breakthrough experiments confirm that CNOP-7 can efficiently and repeatedly separate SF 6 from SF 6 /N 2 mixtures. Molecular simulations reveal the mechanism behind its efficient separation. This work offers fresh perspectives on the development and fabrication of adsorbents for efficient SF 6 sequestration.

This study aimed to identify, assess, and summarize systematic reviews on dietary sodium intake restrictions for patients with heart failure. Literature searches were conducted on Pubmed, CINAHL, ScienceDirect, Cochrane Library, China National Knowledge Infrastructure, and the Wanfang Database up to January 2024. The methodological quality of the included reviews was assessed using the quality assessment tool from the Australian JBI Center for Evidence-Based Healthcare (2016). The results of systematic reviews and meta-analyses were synthesized and presented according to different outcome indicators. Nine systematic reviews were included in this study. The current evidence does not support the fact that dietary sodium intake restrictions for patients with heart failure have a positive impact on mortality rates, rehospitalization rates, and quality of life. Conversely, strict dietary sodium intake restrictions (≤ 2000 mg/day) may increase the risk of death, rehospitalization, and symptom exacerbation. Dietary sodium intake restriction may not have a positive impact on clinical outcomes in patients with heart failure. Nevertheless, more evidence is required to explore the differences in the impact of various levels of dietary sodium restriction on the outcomes and symptom management indicators of patients with heart failure., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This article studies the fuzzy adaptive event-triggered (ET) consensus control issue of nonlinear multiagent systems (NMASs) under jointly connected switching networks. Since the leader and its high-order derivatives are unknown under jointly connected switching networks, a novel distributed ET reference generator equipped with an ET mechanism is constructed to estimate them. Meanwhile, the continuous information transmission among agents is avoided and the network channel utilization is optimized. Subsequently, fuzzy logic systems (FLSs) are employed to approximate unknown dynamics, and a fuzzy adaptive ET consensus control algorithm only using intermittent communication is designed by backstepping control methodology. It is demonstrated that all the closed-loop signals are semi-globally uniformly ultimately bounded (SGUUB), with the tracking errors converging to a small neighborhood around zero. Finally, we apply the developed fuzzy adaptive ET consensus control algorithm to unmanned surface vehicles (USVs), and the simulation results verify the effectiveness of the proposed ET consensus control algorithm.

Addressing the environmental impact of SF 6 , we synthesized a fluorine-functionalized triphenylamine-based nanoporous organic polymer, ANOP-8, at room temperature using N , N , N ', N '-tetraphenylbenzidine and 2,3,4,5,6-pentafluorobenzaldehyde. ANOP-8, which incorporates 14.86% fluorine, has a BET surface area of 694 m 2 g -1 and a robust C-C structure. It achieves SF 6 /N 2 selectivities of 65 and 51 at 298 K and 1 bar through ideal adsorbed and breakthrough experiments, respectively. Molecular simulations have revealed the adsorption mechanisms, underscoring the potential of fluorinated polymers in developing future adsorbents for toxic gases.

Background: Public health is greatly affected by heatwaves, especially as a result of climate change. It is unclear whether heatwaves affect injury hospitalization, especially as developing countries facing the impact of climate change., Objectives: To assess the impact of heatwaves on injury-related hospitalization and the economic burden., Methods: The daily hospitalizations and meteorological data from 2014 to 2019 were collected from 23 study sites in 11 meteorological geographic zones in China. We conducted a two-stage time series analysis based on a time-stratified case-crossover design, combined with DLNM to assess the association between heatwaves and daily injury hospitalization, and to further assess the regional and national economic losses resulting from hospitalization by calculating excess hospitalization costs (direct economic losses) and labor losses (indirect economic losses). To determine the vulnerable groups and areas, we also carried out stratified analyses by age, sex, and region., Results: We found that 6.542% (95%CI: 3.939%, 9.008 %) of injury hospitalization were attributable to heatwaves during warm season (May to September) from 2014 to 2019. Approximately 361,447 injury hospitalizations were attributed to heatwaves each year in China, leading to an excess economic loss of 5.173 (95%CI: 3.104, 7.196) billion CNY, of which 3.114 (95%CI: 1.454, 4.720) billion CNY for males and 4.785 (95%CI: 3.203, 6.321) billion CNY for people aged 15-64 years. The attributable fraction (AF) of injury hospitalizations due to heatwaves was the highest in the plateau mountain climate zone, followed by the subtropical monsoon climate zone and the temperate monsoon climate zone., Conclusions: Heatwaves significantly increase the disease and economic burden of injury hospitalizations, and vary across populations and regions. Our findings implicate the necessity for targeted measures, including raising public awareness, improving healthcare infrastructure, and developing climate resilience policies, to reduce the threat of heatwaves to vulnerable populations and the associated disease and economic burden., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To examine the associations between characteristics of daily rainfall (intensity, duration, and frequency) and all cause, cardiovascular, and respiratory mortality., Design: Two stage time series analysis., Setting: 645 locations across 34 countries or regions., Population: Daily mortality data, comprising a total of 109 954 744 all cause, 31 164 161 cardiovascular, and 11 817 278 respiratory deaths from 1980 to 2020., Main Outcome Measure: Association between daily mortality and rainfall events with return periods (the expected average time between occurrences of an extreme event of a certain magnitude) of one year, two years, and five years, with a 14 day lag period. A continuous relative intensity index was used to generate intensity-response curves to estimate mortality risks at a global scale., Results: During the study period, a total of 50 913 rainfall events with a one year return period, 8362 events with a two year return period, and 3301 events with a five year return period were identified. A day of extreme rainfall with a five year return period was significantly associated with increased daily all cause, cardiovascular, and respiratory mortality, with cumulative relative risks across 0-14 lag days of 1.08 (95% confidence interval 1.05 to 1.11), 1.05 (1.02 to 1.08), and 1.29 (1.19 to 1.39), respectively. Rainfall events with a two year return period were associated with respiratory mortality only, whereas no significant associations were found for events with a one year return period. Non-linear analysis revealed protective effects (relative risk <1) with moderate-heavy rainfall events, shifting to adverse effects (relative risk >1) with extreme intensities. Additionally, mortality risks from extreme rainfall events appeared to be modified by climate type, baseline variability in rainfall, and vegetation coverage, whereas the moderating effects of population density and income level were not significant. Locations with lower variability of baseline rainfall or scarce vegetation coverage showed higher risks., Conclusion: Daily rainfall intensity is associated with varying health effects, with extreme events linked to an increasing relative risk for all cause, cardiovascular, and respiratory mortality. The observed associations varied with local climate and urban infrastructure., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: Support from the Alexander von Humboldt Foundation no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Record-breaking hot weather (exceptional heatwaves) has been increasingly common worldwide, posing a significant threat to human health. However, little is known about the effect of these exceptional heatwaves on mortality in Europe, especially since the coronavirus disease 2019 (COVID-19) outbreak, which converges with climate change to affect healthcare systems and human lives. We collected mortality data of 967 regions in 30 European countries over the last decade (2014-2023) from the Eurostat. A standard time-series analysis was used to estimate the effect of exceptional heatwaves by quasi-Poisson regression model, including the main effect (effect from heatwave intensity) and the added effect (effect from heatwave duration), on mortality for each region during two periods (before and since the COVID-19 outbreak). We used random effects meta-analysis to pool the mortality risk (i.e., relative risk [RR]) and burden (i.e., attributable fraction [AF]) associated with exceptional heatwaves, at the country level and for Europe as a whole. In Europe, the mortality burden attributable to main and added effects increased from 0.492% (95% CI: 0.488%-0.496%) to 1.276% (95% CI: 1.266%-1.285%) and from 0.307% (95% CI: 0.294%-0.318%) to 0.428% (95% CI: 0.407%-0.448%), respectively. Furthermore, substantial variations across countries were observed, with some countries such as France and Spain experiencing a large increase in the mortality burden attributable to exceptional heatwaves since the COVID-19 outbreak. Our findings underscore the urgent need for heat-health actions to consider the multi-effects of exceptional heatwaves amidst a warming climate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Designing adsorbent materials with high SO 2 adsorption capacities and selectivity remains a significant challenge in flue gas desulfurization. This work focuses on developing two nitrogen-rich nanoporous polyaminal networks (NPANs), which demonstrate promising capabilities for SO 2 adsorption and separation. Two nitrogen-rich nanoporous polyaminal networks, NPAN-5 and NPAN-6, were synthesized via a one-pot method using thiophene-2,5-dicarbaldehyde and furan-2,5-dicarbaldehyde with 1,4-bis(2,4-diamino-1,3,5-triazine)-benzene, respectively. The Brunauer-Emmett-Teller (BET) specific surface areas of NPANs range from 838 to 956 m 2 ·g -1 . At 298 K and pressures of 0.1 and 1.0 bar, NPAN-5, featuring thiophene units, demonstrates a SO 2 adsorption uptake of 5.14 and 9.63 mmol·g -1 , respectively, surpassing many previously reported materials. Furthermore, at room temperature, NPAN-6, containing furan moieties, exhibits unprecedented selectivity for SO 2 over CO 2 and N 2 , with ratios reaching up to 78 and 9321, respectively. Dynamic breakthrough experiments reveal that NPANs effectively separate SO 2 from a ternary gas mixture comprising SO 2 , CO 2 , and N 2 at concentrations of 0.2, 10, and 89.8%, respectively. Notably, NPAN-6 achieves a prolonged SO 2 retention time of 218 min·g -1 and a saturation adsorption uptake of 0.42 mmol·g -1 . The remarkable SO 2 adsorption capacities and selectivities demonstrated by these nitrogen-rich nanoporous polyaminal networks underscore their potential to revolutionize industrial flue gas desulfurization.

Background: Studies have shown that abnormal temperature at night is a risk factor for respiratory health. However, there is limited evidence on the impact of hot and cold nights on cause-specific diseases such as pneumonia, which is a leading cause of morbidity and mortality in children., Methods: We collected daily data on pneumonia hospitalisations in children under five years from 2011 to 2017 in three low-, middle- and high-income countries (Bangladesh, China, and Australia). The intensity of hot and cold nights was measured by excess temperature. A space-time-stratified case-crossover analysis was used to estimate the association between hot and cold nights and childhood pneumonia hospitalisations. We further estimated the fraction of childhood pneumonia hospitalisations attributable to hot and cold nights., Results: Both hot and cold nights were associated with an increased risk of hospitalisations for childhood pneumonia in low-, middle-, and high-income countries, with a greater disease burden from hot nights. Specifically, the fraction of childhood pneumonia attributable to hot nights was the largest in Australia [21.2%, 95% confidence interval (CI): 11.8%-28.1%], followed by Bangladesh (15.2%, 95% CI: 4.1%-23.8%) and China (2.7%, 95% CI: 0.4%-4.7%). Additionally, the fraction of childhood pneumonia attributable to cold nights was 1.3% (95% CI: 0.4%-2.0%) in Bangladesh and 0.4% (95% CI: 0.1%-0.7%) in China., Conclusion: This multi-country study suggests that hot and cold nights are not only associated with a higher risk of pneumonia hospitalisations in children but also responsible for substantial fraction of hospitalisations, with a greater impact from hot nights., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is an inhibitory receptor expressed on immune cells. We evaluated LAIR1 in placentas from preeclamptic or small for gestational age (SGA) pregnancies, and placental explant model (1 % O 2 , IL6 and TNFα, or control). LAIR1 mRNA was reduced in placentas from preeclamptic (p < 0.0001, n = 78) and SGA (p < 0.0001, n = 32) pregnancies. LAIR1 protein expression was reduced in placentas from preeclampsia (p < 0.0001, n = 43) and SGA (p = 0.009, n = 10) pregnancies. Hypoxia (1 % O 2 ) reduced LAIR1 mRNA expression in placental explants (p = 0.008). These findings suggest hypoxia modulates LAIR1 expression in the placenta., Competing Interests: Declaration of competing Interest None., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Dysregulated progenitor cell populations may contribute to poor placental development and placental insufficiency pathogenesis. Side-population cells possess progenitor properties. Recent human trophoblast side-population isolation identified enrichment of 8 specific genes (CXCL8, ELL2, GATA6, HK2, HLA-DPB1, INTS6, SERPINE3 and UPP1) (Gamage et al. 2020, Stem Cell Rev Rep). We characterised these trophoblast side-population markers in human placenta and in placental insufficiency disorders: preeclampsia and fetal growth restriction (FGR). Trophoblast side-population markers localised to mononuclear trophoblasts lining the placental villous basement membrane in preterm control, preeclamptic and FGR placental sections (n = 3, panel of 3 markers/serial section). Analysis of single-cell transcriptomics of an organoid human trophoblast stem cell (hTSC) to extravillous trophoblast (EVT) differentiation model (Shannon et al. 2022, Development) identified that all side-population genes were enriched in mononuclear trophoblast and trophoblasts committed to differentiation under hTSC culture conditions. In vitro validation via 96 h time course hTSC differentiation to EVTs or syncytiotrophoblasts (n = 5) demonstrated ELL2 and HK2 increased with differentiation (p < 0.0024, p < 0.0039 respectively). CXCL8 and HLA-DPB1 were downregulated (p < 0.030, p < 0.011 respectively). GATA6 and INTS6 increased with EVT differentiation only, and UPP1 reduced with syncytialisation. SERPINE3 was undetectable. Trophoblast side-population marker mRNA was measured in human placentas (< 34-weeks' gestation; n = 78 preeclampsia, n = 30 FGR, and n = 18 gestation-matched controls). ELL2, HK2 and CXCL8 were elevated in preeclamptic (p = 0.0006, p < 0.0001, p = 0.0335 respectively) and FGR placentas (p = 0.0065, p < 0.0001, p = 0.0001 respectively) versus controls. Placental GATA6 was reduced in pregnancies with preeclampsia and FGR (p = 0.0014, p = 0.0146 respectively). Placental INTS6 was reduced with FGR only (p < 0.0001). This study identified the localisation of a unique trophoblast subset enriched for side-population markers. Aberrant expression of some side-population markers may indicate disruptions to unique trophoblast subtypes in placental insufficiency., (© 2024. The Author(s).)

Epidemiological evidence on the impact of airborne organic pollutants on lung function among the elderly is limited, and their underlying biological mechanisms remain largely unexplored. Herein, a longitudinal panel study was conducted in Jinan, Shandong Province, China, involving 76 healthy older adults monitored over a span of five months repetitively. We systematically evaluated personal exposure to a diverse range of airborne organic pollutants using a wearable passive sampler and their effects on lung function. Participants' pulmonary function indicators were assessed, complemented by comprehensive multi-omics analyses of blood and urine samples. Leveraging the power of interaction analysis, causal inference test (CIT), and integrative pathway analysis (IPA), we explored intricate relationships between specific organic pollutants, biomolecules, and lung function deterioration, elucidating the biological mechanisms underpinning the adverse impacts of these pollutants. We observed that bis (2-chloro-1-methylethyl) ether (BCIE) was significantly associated with negative changes in the forced vital capacity (FVC), with glycerolipids mitigating this adverse effect. Additionally, 31 canonical pathways [e.g., high mobility group box 1 (HMGB1) signaling, phosphatidylinositol 3-kinase (PI3K)/AKT pathway, epithelial mesenchymal transition, and heme and nicotinamide adenine dinucleotide (NAD) biosynthesis] were identified as potential mechanisms. These findings may hold significant implications for developing effective strategies to prevent and mitigate respiratory health risks arising from exposure to such airborne pollutants. However, due to certain limitations of the study, our results should be interpreted with caution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy., Methods: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes. Results from both countries were then combined in a meta-analysis using a random effects model., Results: The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48])., Conclusions: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes., (© 2024. The Author(s).)

Five types of sulfobutylether-β-cyclodextrin (SBE-β-CD) and carboxymethyl-β-cyclodextrin (CM-β-CD) with different degrees of substitution were synthesized, and six and five racemates were respectively chosen to study the influence of the degree of substitution on the enantioseparation factor. The synthesized SBE-β-CD and CM-β-CD were characterized using 1 H NMR spectroscopy and mass spectrometry. The results indicated that the influence of the degree of substitution on enantioseparation for distinct racemates exhibited significant variability. Increasing the degree of substitution of CM-β-CD led to an increasing enantioseparation factor, while SBE-β-CD with a specific degree of substitution provided the optimum enantioseparation factor for some racemates. The optimum enantioseparation factors of N-methyl duloxetine and duloxetine were obtained when a relatively low degree of substitution (DS = 3.5) was selected. And the optimum enantioseparation factor was obtained with a relatively high degree of substitution (DS = 7.5). SBE-β-CD with a low substitution degree of 3.5 was chosen to optimize the countercurrent chromatographic enantioseparation of N-methyl-duloxetine, which resulted in a significant improvement in peak resolution from 0.51 to 0.83. Molecular docking was used to construct three SBE-β-CDs with different degrees and distributions of substitution, and a good agreement was found between the docking results and the experimental results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: The primary objective of this study was to determine the frequency and nature of complications that occur during intrathecal baclofen (ITB) therapy, including nonsurgical complications as well as complications associated with both implantation surgeries and subsequent revisions., Methods: The authors retrospectively reviewed the medical records of all patients who had baclofen pumps implanted at a tertiary children's hospital from 2006 through June 2019. The study employed appropriate descriptive statistics and statistical models to analyze patient demographics, improvements in tone, and clinical complications. The authors evaluated the associations of complications as well as changes in modified Ashworth Scale (MAS) scores with various preexisting conditions (e.g., presence of gastrostomy tubes [G-tubes] and ventriculoperitoneal [VP] shunts) and surgical variations (e.g., use of newer [Ascenda] catheters and subfascial versus subcutaneous catheter tunneling)., Results: One hundred forty-two pumps were implanted. Complications occurred in 111 patients (78.2%). The most frequent complications were catheter complications and pseudomeningoceles, each of which occurred in 63 (44%) patients. On multivariable analysis, pseudomeningoceles and percutaneous CSF leaks were significantly less likely when intrathecal catheters were placed via laminotomy versus spinal needle (OR 4.6, p = 0.044), and when catheters were passed from the posterior incision to the abdominal pump pocket deep to the thoracolumbar fascia rather than superficial to it (OR 2.7, p = 0.008). Preexisting G-tubes and VP shunts at the time of pump implantation were not associated with a significantly increased likelihood of pump malfunction or infection. Ascenda catheters were significantly less likely to have disconnections (p < 0.001) and obstructions (p = 0.016), and overall were less likely to have any catheter-related complications (p = 0.01). Patients with preexisting VP shunts at the time of implantation had a significantly greater mean decrease in MAS scores in both their lower extremities (1.8, p = 0.003) and upper extremities (1.3, p = 0.002) than did patients without shunts., Conclusions: Various complications are associated with ITB therapy, most commonly catheter complications and pseudomeningoceles. There have been fewer catheter complications associated with the newest catheter model, while pseudomeningoceles have become less frequent since the surgical technique was modified to prevent them. VP shunts and G-tubes are not associated with significantly higher complication rates and shunts seem to be associated with greater efficacy of ITB therapy, as represented by a greater mean improvement in MAS scores.

There is a resurgence of research interest in inherently chiral calixarenes and heteracalixaromatics. However, the examples of macrocyclic ring-expanded homocalixarenes and heterocalixaromatics of inherent chirality are not known. Here we report an efficient method to construct inherently chiral N 2 ,O 2 -linked homo-heteracalixaromatics from reductive amination reactions between bis-aldehydes and aliphatic diamines. Examples of post-macrocyclization derivatization were also demonstrated. Enantiomers were obtained from resolution and did not undergo racemization at an elevated temperature. This study provides a new strategy to design novel and functional inherently chiral macrocycles that have potential applications in supramolecular chemistry.

Purpose: Accurate preoperative identification of Human epidermal growth factor receptor 2 (HER2) low expression breast cancer (BC) is critical for clinical decision-making. Our aim was to use machine learning methods to develop and validate an ultrasound-based radiomics nomogram for predicting HER2-low expression in BC., Methods: In this retrospective study, 222 patients (108 HER2-0 expression and 114 HER2-low expression) with BC were included. The enrolled patients were randomly divided into a training cohort and a test cohort with a ratio of 8:2. The tumor region of interest was manually delineated from ultrasound image, and radiomics features were subsequently extracted. The features underwent dimension reduction using the least absolute shrinkage and selection operator (LASSO) algorithm, and rad-score were calculated. Five machine learning algorithms were applied for training, and the algorithm demonstrating the best performance was selected to construct a radiomics (USR) model. Clinical risk factors were integrated with rad-score to construct the prediction model, and a nomogram was plotted. The performance of the nomogram was assessed using receiver operating characteristic curve and decision curve analysis., Results: A total of 480 radiomics features were extracted, out of which 11 were screened out. The majority of the extracted features were wavelet features. Subsequently, the USR model was established, and rad-scores were computed. The nomogram, incorporating rad-score, tumor shape, border, and microcalcification, achieved the best performance in both the training cohort (AUC 0.89; 95%CI 0.836-0.936) and the test cohort (AUC 0.84; 95%CI 0.722-0.958), outperforming both the USR model and clinical model. The calibration curves showed satisfactory consistency, and DCA confirmed the clinical utility of the nomogram., Conclusion: The nomogram model based on ultrasound radiomics exhibited high prediction value for HER2-low BC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wu, Zu, Li, Zhang, Ren, Qian, Tong and Li.)

Small intestinal neuroendocrine tumors (SI-NETs) are a group of rare and significantly heterogeneous tumors with limited research currently available. This study aimed to investigate the incidence, survival, and prognostic factors of SI-NETs. We selected data from the surveillance, epidemiology, and end results (SEER) database between 2000 and 2019 and evaluated the incidence trend of SI-NETs during this period. We utilized the Kaplan-Meier method to examine the association between clinical variables and survival rates. Based on the multivariable Cox regression analysis results, we developed a nomogram to predict the 1-, 2-, and 3-year cancer-specific survival (CSS) of SI-NETs patients. We evaluated the consistency, accuracy, and clinical utility of the nomogram by drawing calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) curves. The incidence of SI-NETs showed an upward trend in recent years. Age, grade, T stage, M stage, and primary tumor surgery were independent risk factors for CSS in SI-NETs patients. The nomogram model based on these risk factors showed high accuracy and clinical benefit. SI-NETs are rare tumors with an increasing incidence rate. The nomogram model is expected to be an effective tool for personalized prognosis prediction in SI-NETs patients, which may benefit clinical decision-making., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Existing literature on the prevalence of middle turbinate pneumatization, or concha bullosa (CB), in the pediatric population is limited. CB is an anatomic variant important to identify prior to sinonasal surgery and is often associated with congenital nasal septal deviation (SD). This paper aims to describe the prevalence of CB in the pediatric population on head imaging., Methods: A retrospective chart review was performed for 695 children undergoing CT head for trauma from 2021 to 2022. Nearly equal numbers of males and females were evaluated, with at least 19-20 per year from 0.5 to 18 years. Patients with significant facial fractures, sinusitis, craniofacial syndromes, prior sinus surgery, and sinonasal masses were excluded. Two pediatric neuroradiologists evaluated the CTs. CB was defined as aeration >50 % of the vertical height of the middle turbinate., Results: In this study, 384 patients were included. The prevalence of CB was 153 (39.8 %), which was significantly higher in children >4 years (p < 0.0001). Lamellar type CB was the most common, present in 160 out of 768 middle turbinates assessed (20.8 %). SD occurred in 60 (39.2 %) patients with CB and was more commonly contralateral to the CB., Conclusions: The prevalence of CB in the pediatric population is at the lower range of what is reported in the adult literature. The most common type of CB in patients is lamellar. Similar to previous studies, there is an association between CB and contralateral SD. Finally, there is a positive correlation between the severity of CB and the severity of SD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Lattice structures, comprising nodes and struts arranged in an array, are renowned for their lightweight and unique mechanical deformation characteristics. Previous studies on lattice structures have revealed that failure often originates from stress concentration points and spreads throughout the material. This results in collapse failure, similar to the accumulation of damage at defects in metallic crystals. Here the precipitation hardening mechanism found in crystalline materials is employed to deflect the initial failure path, through the strategic placement of strengthening units at stress concentration points using the finite element method. Both the mesostructure, inspired by the arrangement of crystals, and the inherent microstructure of the base materials have played crucial roles in shaping the mechanical properties of the macro-lattices. As a result, a groundbreaking multiscale hierarchical design methodology, offering a spectrum of design concepts for engineering materials with desired properties is introduced., (© 2024 Wiley‐VCH GmbH.)

Background and Aim: Allergic asthma is a primary type of asthma and characterized by T helper 2 (Th2) cells -mediated inflammation. Tripartite motif containing 8 (TRIM8) protein is involved in immunoreaction and inflammatory response in many diseases. However, its role in allergic asthma remains unclear. Medical databank showed that TRIM8 was increased in lung of ovalbumin (OVA)-challenged mice. This study aimed to elucidate the effects of TRIM8 on allergic asthma and Th2 development., Methods: Asthma were induced by OVA challenge in mice, and the adenovirus vector loaded with TRIM8 knockdown sequence was delivered into asthma mice by nasal inhalation. The percentage of Th2 cells in lung was assessed by flow cytometric analysis, and the contents of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF) were assessed with ELISA. In vitro Th2 induction was performed in CD4 + cells from mouse spleen, the expression of Th2 molecules (IL-4, IL-5 and GATA binding protein 3 (GATA3)) were measured by real-time PCR. In addition, the nuclear factor-kappa B (NF-κB)/nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) signaling was determined., Results: TRIM8 was highly expressed in the lung tissues of asthmatic mice and Th2-induced CD4 + cells. OVA challenge-induced Th2 development and Th2 cytokine secretion were restrained by silencing of TRIM8 in vivo. Similarly, the Th2 differentiation in vitro was also suppressed by TRIM8 knockdown. TRIM8 inhibited the NF-κB/NLRP3 activity by blocking transforming growth factor-beta-activated kinase 1 (TAK1), and the effects of TRIM8 were abrogated by overexpression of NLRP3., Conclusions: Silencing TRIM8 relieved the asthmatic injury in mice and excessive Th2 development via inhibiting the NF-κB/NLRP3 pathway. It is indicated that TRIM8 may contribute to the airway inflammation in allergic asthma via activating the NF-κB/NLRP3 signaling pathway. The current study provided a novel potential target for allergic asthma treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Major depressive disorder (MDD) is often accompanied by psychotic symptoms. However, few studies have examined the relationship between psychotic symptoms and endocrine factors in adolescent patients with MDD. Therefore, this study aimed to investigate the prevalence and related endocrine clinical factors of psychotic symptoms in Chinese adolescent patients with MDD., Methods: In total, 601 patients (aged 12-18) with MDD were recruited. The Patient Health Questionnaire - 9 items (PHQ - 9) was utilized for assessing depressive symptoms. Psychotic symptoms were assessed through clinical interviews. Prolactin (PRL), thyroid-stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), and free thyroxine (FT4) were also measured., Results: The incidence of psychotic symptoms in adolescent patients with MDD was 22.6%. The findings demonstrated that age, self-harming behavior, PHQ-9 score, FT4, and normalized PRL were independently associated with psychotic symptoms in patients with MDD (All p < 0.05)., Conclusions: PRL and FT4 levels are more likely to be abnormally elevated in major depressive adolescents with psychotic symptoms. Prolactin and thyroid hormones in patients with MDD should be paid more attention., (© 2024. The Author(s).)

Objective: The EAT-Lancet Commission has proposed an EAT-Lancet diet (ELD), also known as a planetary health diet (PHD), which is environmentally sustainable and promotes human health. However, the association between this diet and the risk of hypertension remains unclear. This study aimed to determine whether adherence to ELD was associated with a lower risk of hypertension., Methods: 11,402 adults without hypertension at baseline from the China Health and Nutrition Survey were included. The PHD score was used to evaluate ELD adherence, with higher scores reflecting better compliance. Cox proportional hazards regression analysis was utilized to estimate the hazard ratio (HR) with a 95% confidence interval (CI). Additionally, a subgroup analysis was performed to identify the possible effect modifiers, and a mediation analysis was conducted to explore the mediation effects of anthropometric measurements on the association between ELD and hypertension., Results: A total of 3993 participants (35%) developed hypertension during 93,058 person-years of follow-up. In the covariate-adjusted model, hypertension risk was reduced in the highest quartile participants compared to the lowest quartile of the PHD score (adjusted HR: 0.79, 95%CI: 0.71-0.87; P -trend < 0.001), which remained significant after sensitivity analysis. Notably, the association was also observed in isolated systolic hypertension, isolated diastolic hypertension, and systolic-diastolic hypertension. Subgroup analysis revealed that the inverse association between the PHD score and hypertension risk was more pronounced in nonsmokers and high-sodium intake consumers than in smokers and low-sodium consumers ( P -interaction < 0.05). Additionally, mediation analysis revealed that 23.3% of the association between the PHD score and hypertension risk was mediated by the waist-to-height ratio., Conclusion: Our findings suggest that a higher adherence to ELD is associated with a lower risk of hypertension. These results emphasize that ELD may serve as a potential strategy to prevent hypertension.

Sustainable production of edible microbial proteins and red food colorants is an important demand for future food. Therefore, creation of a chassis strain that can efficiently synthesize both products is extremely necessary and meaningful. To realize this envision, a CRISPR/Cas9-based visual multicopy integration system was successfully developed in Fusarium venenatum . Subsequently, the de novo synthesis of the red food colorant betanin was achieved in the engineered F. venenatum using the above system. After fermentation optimization, the final yields of betanin and mycoprotein reached 1.91 and 9.53 g/L, respectively, when the constant pH naturally decreased from 6 to 4 without the addition of acid after 48 h of fermentation. These results determine a highly suitable chassis strain for the microbial biomanufacturing of betanin, and the obtained engineered strain here is expected to expand the application prospect and improve economic returns of F. venenatum in the field of future food.

Aims: Chronic pain is highly associated with anxiety. Electroacupuncture (EA) is effective in relieving pain and anxiety. Currently, little is known about the neural mechanisms underlying the comorbidity of chronic pain and anxiety and the EA mechanism. This study investigated a potential neural circuit underlying the comorbid and EA mechanisms., Methods: Spared nerve injury (SNI) surgery established the chronic neuropathic pain mouse model. The neural circuit was activated or inhibited using the chemogenetic method to explore the relationship between the neural circuit and mechanical allodynia and anxiety-like behaviors. EA combined with the chemogenetic method was used to explore whether the effects of EA were related to this neural circuit., Results: EA attenuated mechanical allodynia and anxiety-like behaviors in SNI mice, which may be associated with the activity of CaMKII neurons in the basolateral amygdala (BLA). Inhibition of BLA CaMKII -rACC induced mechanical allodynia and anxiety-like behaviors in sham mice. Activation of the BLA CaMKII -rACC alleviated neuropathic pain and anxiety-like behaviors in SNI mice. The analgesic and anxiolytic effects of 2 Hz EA were antagonized by the inhibition of the BLA CaMKII -rACC., Conclusion: BLA CaMKII -rACC mediates mechanical allodynia and anxiety-like behaviors. The analgesic and anxiolytic effects of 2 Hz EA may be associated with the BLA CaMKII -rACC., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Nearly half of patients with diabetes experience diabetic peripheral neuropathy (DPN), resulting in a mere 53% survival rate within 3 years. Aberrations in coagulation function have been implicated in the pathogenesis of microvascular complications, prompting the need for a thorough investigation into its role as a contributing factor in the development and progression of DPN., Methods: Data were gathered from 1211 type 2 diabetes patients admitted to five centers from September 2018 to October 2022 in China. DPN was evaluated by symptoms and electromyography. Motor and sensory nerve conduction velocity (NCV) was appraised and the NCV sum score was calculated for the median, ulnar, and peroneal motor or sensory nerves., Results: Patients with DPN exhibited alterations in coagulation function. (i) Specifically, they exhibited prolonged thrombin time (p = 0.012), elevated fibrinogen (p < 0.001), and shortened activated partial thromboplastin time (APTT; p = 0.026) when compared to the control group. (ii) After accounting for potential confounders in linear regression, fibrinogen, and D-dimer were negatively related to the motor NCV, motor amplitude values, and mean velocity and amplitude. Also, fibrinogen was associated with higher Michigan neuropathy screening instrument (MNSI) scores (β 0.140; p = 0.001). This result of fibrinogen can be validated in the validation cohort with 317 diabetic patients. (iii) Fibrinogen was independently associated with the risk of DPN (OR 1.172; p = 0.035). In the total age group, DPN occurred at a slower rate until the predicted fibrinogen level reached around 3.75 g/L, after which the risk sharply escalated., Conclusions: Coagulation function is warranted to be concerned in patients with type 2 diabetes to predict and prevent the occurrence of DPN in clinical practice., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Environmental contaminants (ECs) are increasingly recognized as crucial drivers of dyslipidemia and cardiovascular disease (CVD), but the comprehensive impact spectrum and interlinking mechanisms remain uncertain., Objectives: We aimed to systematically evaluate the association between exposure to 80 ECs across seven divergent categories and markers of dyslipidemia and investigate their underpinning biomolecular mechanisms via an unbiased integrative approach of internal chemical exposome and multi-omics., Methods: A longitudinal study involving 76 healthy older adults was conducted in Jinan, China, and participants were followed five times from 10 September 2018 to 19 January 2019 in 1-month intervals. A broad spectrum of seven chemical categories covering the prototypes and metabolites of 102 ECs in serum or urine as well as six serum dyslipidemia markers [total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein (Apo)A1, ApoB, and ApoE4] were measured. Multi-omics, including the blood transcriptome, serum/urine metabolome, and serum lipidome, were profiled concurrently. Exposome-wide association study and the deletion/substitution/addition algorithms were applied to explore the associations between 80 EC exposures detection frequency > 50 % and dyslipidemia markers. Weighted quantile sum regression was used to assess the mixture effects and relative contributions. Multi-omics profiling, causal inference model, and pathway analysis were conducted to interpret the mediating biomolecules and underlying mechanisms. Examination of cytokines and electrocardiograms was further conducted to validate the observed associations and biomolecular pathways., Results: Eight main ECs [1-naphthalene, 1-pyrene, 2-fluorene, dibutyl phosphate, tri-phenyl phosphate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, chromium, and vanadium] were significantly associated with most dyslipidemia markers. Multi-omics indicated that the associations were mediated by endogenous biomolecules and pathways, primarily pertinent to CVD, inflammation, and metabolism. Clinical measures of cytokines and electrocardiograms further cross-validated the association of these exogenous ECs with systemic inflammation and cardiac function, demonstrating their potential mechanisms in driving dyslipidemia pathogenesis., Discussion: It is imperative to prioritize mitigating exposure to these ECs in the primary prevention and control of the dyslipidemia epidemic. https://doi.org/10.1289/EHP13864.

Background: Intensive care unit (ICU) delirium is a common complication in older critically ill patients that has a significant impact. The Family Confusion Assessment Method (FAM-CAM) is a vital tool for assisting family members in identifying delirium; however, no study has yet been reported on the Chinese version of the scale., Objectives: The objective of this study was to translate the FAM-CAM into a Chinese version and to verify its effectiveness for delirium detection in an online patient visit setting., Methods: This was a cross-sectional study. The FAM-CAM was translated to Chinese according to the International Society for Pharmacoeconomics and Outcomes Research guidelines. Patients and family members were recruited to participate in delirium assessments in three ICUs of one hospital. Family members then used the Chinese version of the FAM-CAM to assess for delirium via online visitation, and ICU nurses assessed patients for delirium using the Intensive Care Delirium Screening Checklist (ICDSC). Results were then compared between family members' and nurses' assessments., Results: Overall, 190 critically ill patients and 190 family members were included, of whom 117 (61.6%) were assessed for delirium using the Intensive Care Delirium Screening Checklist. The Cohen's kappa coefficient between the Intensive Care Delirium Screening Checklist and FAM-CAM was 0.759 (P < 0.01). The sensitivity of the Chinese version of the FAM-CAM was 0.880, specificity was 0.890, positive predictive value was 0.928, negative predictive value was 0.823, and area under the receiver operating characteristic curve was 0.881 (95% confidence interval: 0.872-0.935, P < 0.01)., Conclusion: The Chinese version of the FAM-CAM was shown to effectively help families detect delirium and was suggested as a crucial tool for assisting ICU nurses in the early identification of delirium. This tool may effectively be used to assess delirium during online visits., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Tinnitus and misophonia are important "sound annoyance" disorders in pediatric otolaryngology and audiology practices. There is scant published literature to suggest increased anxiety and depression symptoms in these disorders. This study aimed at assessing the clinical characteristics of these 2 disorders and their prevalence in mental health-related symptoms in a 2-year retrospective chart review of a multi-disciplinary (otolaryngology, audiology, and psychology) clinic cohort. Analyses were based on 54 (tinnitus = 33 and misophonia = 21) children consisting of 19 males and 35 females with a mean age (standard deviation) of 14.3 (3.0) years. The entire cohort was negatively affected by diagnosis-based symptom severity instruments as assessed by Tinnitus Functional Index and Amsterdam Misophonia Scale. Both subgroups exhibited elevated anxiety and depression symptoms in psychometric instruments as assessed by Screen for Child Anxiety Related Emotional Disorders and Short Mood and Feelings Questionnaire. Evidence-based management of these disorders is lacking, and clinical trials are needed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes., Data Sources: MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023., Study Eligibility Criteria: Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review., Methods: Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials., Results: A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias., Conclusion: In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Soil organic carbon and nitrogen play pivotal roles as indicators of soil quality and ecological functioning in wetlands. The escalating impact of human activities and climate change has led to a severe degradation of wetland soils, particularly in semi-arid regions. However, an understanding of the factors governing the dynamics of total soil organic carbon (TSOC) and total soil nitrogen (TSN) in semi-arid areas remains elusive, impeding a comprehensive understanding of wetland ecological functions. The present study investigated variations in TSOC and TSN content as well as vegetation and soil physicochemical properties under five different land management practices (mowed wetlands, mowed and slightly grazed wetlands, moderately grazed wetlands, heavily grazed wetlands, and natural wetlands unaffected by human interference) in the semi-arid Songnen Plain region of China. The results revealed significant decreases in TSOC and TSN content within managed wetlands compared to natural wetlands. Moreover, positive correlations were observed between pairs of SOC-TN or their storage values for SOC (TSOC)-TN (TSN). Furthermore, TSOC and TSN exhibited significant positive associations with aboveground and belowground biomass levels, stem C:N, stem C:P, soil C:P, and soil N:P. Additionally, redundancy analysis indicated that species diversity accounted for 37.4% of the variations in TSOC-TSN while belowground biomass accounted for 8.5% of the variations. Furthermore, nutrient content within stems (particularly N content and C:P) contributed to a 37.2% variation in TSOC and TSN whereas root nutrient content (especially N:P, C:N, and C:P) contributed to a 15.3% variation. Soil C:P, C:N, and total phosphorous (TP) content accounted for 65.7%, 9.6%, and 7.5% of variations of TSOC and TSN, respectively. Besides, variation partitioning analysis revealed that plant community characteristics, community nutrient content, and soil physicochemical properties collectively influenced the dynamics of TSOC and TSN. Among these factors, soil physicochemical properties emerged as the primary drivers of carbon and nitrogen dynamics in degraded wetlands in semi-arid regions. The impact on TSN was more pronounced than that of TSOC. This study provides valuable insights for understanding the processes and mechanisms underlying carbon and nitrogen accumulation in degraded wetlands, facilitating the development of regionally adaptive management plans under different management practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The interface connects the reinforced phase and the matrix of materials, with its microstructure and interfacial configurations directly impacting the overall performance of composites. In this study, utilizing seven atomic layers of Mg(0001) and Ti(0001) surface slab models, four different Mg(0001)/Ti(0001) interfaces with varying atomic stacking configurations were constructed. The calculated interface adhesion energy and electronic bonding information of the Mg(0001)/Ti(0001) interface reveal that the HCP2 interface configuration exhibits the best stability. Moreover, Si, Ca, Sc, V, Cr, Mn, Fe, Cu, Zn, Y, Zr, Nb, Mo, Sn, La, Ce, Nd, and Gd elements are introduced into the Mg/Ti interface layer or interfacial sublayer of the HCP2 configurations, and their interfacial segregation behavior is investigated systematically. The results indicate that Gd atom doping in the Mg(0001)/Ti(0001) interface exhibits the smallest heat of segregation, with a value of -5.83 eV. However, Ca and La atom doping in the Mg(0001)/Ti(0001) interface show larger heat of segregation, with values of 0.84 and 0.63 eV, respectively. This implies that the Gd atom exhibits a higher propensity to segregate at the interface, whereas the Ca and La atoms are less inclined to segregate. Moreover, the electronic density is thoroughly analyzed to elucidate the interfacial segregation behavior. The research findings presented in this paper offer valuable guidance and insights for designing the composition of magnesium-based composites.

The combination of the dark fiber in existing Optical Fiber Composite Overhead Ground Wire (OPGW) with Distributed Optical Fiber Sensing (DOFS) technology can be used to enable online monitoring and provide early warnings of anomalies in high-voltage transmission lines. Accurate mapping of the optical cable length to the geographic coordinates of actual towers is a key factor in achieving this goal. This paper discusses the principle of using a DOFS system for transmission line tower positioning and presents four available positioning features. To overcome the limitations of single physical parameter positioning, this paper presents a self-developed hybrid DOFS that simultaneously captures Rayleigh backscattering and Brillouin scattering signals. Several physical parameters, including temperature, strain, and vibration, are acquired synchronously. Through hybrid multi-parameter analysis, the rapid and accurate positioning of OPGW line towers is achieved. Experimental results have shown that the proposed method, based on the hybrid DOFS system, can locate up to 82 towers, while the traditional method could only identify 12. The hybrid system was able to complete 80% of the tension towers in 40 h. This paper presents a novel multi-parameter localization method that has the potential to significantly improve the efficiency and reliability of grid operation and maintenance.

Background: China published its inaugural national heat-health action plan (HHAP) in 2023, but the mortality burden associated with temperatures exceeding the heat alert thresholds specified by this HHAP (maximum temperatures >35, 37, or 40 °C) remains unknown. We aimed to estimate the historical and future mortality burden associated with temperatures above the heat alert thresholds of the Chinese national HHAP., Methods: We conducted time-series analyses to estimate the mortality burden associated with temperatures exceeding the three heat alert thresholds from 2016 to 2019 in Jiangsu Province (including 13 cities, population ∼80.7 million), China. A quasi-Poisson regression in conjunction with a distributed lag non-linear model was used to estimate the dose-response association between maximum temperature and mortality risk from 2016 to 2019, adjusting for potential covariates. We then projected the future mortality burden associated with temperatures exceeding these thresholds under three distinct levels of greenhouse gas (GHG) emission scenarios via scenario shared socioeconomic pathways [SSP] 1-2.6 (low), SSP2-4.5 (intermediate), and SSP5-8.5 (high), respectively, by assuming that there will be no adaptation to heat. Climate scenarios derived from the General Circulation Model (GCM) under the Coupled Model Intercomparison Project Phase 6 (CMIP6) were used., Results: From 2016 to 2019, temperatures above 35 °C were associated with 0.51% of mortality, including 0.40% associated with 35 °C-37 °C and 0.11% associated with >37 °C. Heat-related mortality risk was most prominent in those who were single/divorced/widowed and had <10 years of education. Under SSP2-4.5, compared with the 2020s, the excess mortality associated with >37 °C would increase by 1.4 times in the 2050s and 1.7 times in the 2090s. Under SSP5-8.5, the annual number of days with maximum temperature >37 °C would approximately double every 20 years (67 days annually in the 2090s). Consequently, compared with the 2020s, the excess mortality associated with >37 °C would increase by 2.8 times in the 2050s and 18.4 times in the 2090s., Conclusion: Significant mortality risk is associated with temperatures above the lowest heat alert threshold of the Chinese national HHAP (35 °C). If the high GHG emission scenario occurred, the annual number of days and excess mortality associated with maximum temperatures >37 °C would largely increase in the coming decades., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Excessive intraoperative bleeding remains a challenge in limb surgeries. The exsanguination tourniquet ring has emerged as a potential solution for effective exsanguination and hemostasis. This study aims to evaluate its efficacy and safety compared to the conventional exsanguination and hemostasis approach (pneumatic tourniquet combined with Esmarch bandage)., Methods: This randomized controlled trial evaluates the exsanguination tourniquet ring's effectiveness and safety versus the conventional approach in 220 participants undergoing various limb surgeries. Allocation included experimental and control groups, assesses through efficacy (including intraoperative and total blood loss, hemoglobin levels, and exsanguination and hemostasis effectiveness) and safety (adverse event occurrence) indicators., Results: The experimental group (n = 110) utilizes the exsanguination tourniquet ring, while the control group (n = 110) employs the conventional approach. As for intraoperative blood loss, the experimental group is non-inferior to the control group (p-value < 0.001). While no significant difference is found in total blood loss (for the full analysis set, p-value = 0.442; for the per protocol set, p-value = 0.976) and differences in postoperative and preoperative hemoglobin levels (for the full analysis set, p-value = 0.502; for the per protocol set, p-value = 0.928). Regarding exsanguination and hemostasis effectiveness, the full analysis set reveals significantly superior ratings in the experimental group compared to the control group (p-value = 0.002 < 0.05), while the per protocol set analysis indicates no significant difference between the groups (p-value = 0.504). As for safety indicators, adverse events related to the device are minimal in two groups, with only one severe event unrelated to the device., Conclusions: The exsanguination tourniquet ring is an effective and safe device for intraoperative blood loss control in various limb surgeries., Trial Registration: Comparison of Exsanguination and Hemostasis Devices for Limb Surgery A Prospective Multicenter Randomized Controlled Study, ChiCTR2300077998, 11/27/2023., (© 2024. The Author(s).)

Fermented soybeans are popular among many for their rich soy sauce-like aroma. However, the precise composition of this aroma remains elusive, with key aroma compounds unidentified. In this study, we screened the candidate genes ilvA and serA in BJ3-2 based on previous multi-omics data, and we constructed three mutant strains, BJ3-2- ΔserA , BJ3-2- ΔilvA , and BJ3-2- ΔserAΔilvA , using homologous recombination to fermented soybeans with varying intensities of soy sauce-like aroma. Our objective was to analyze samples that exhibited different aroma intensities resulting from the fermented soybeans of BJ3-2 and its mutant strains, thereby exploring the key flavor compounds influencing soy sauce-like aroma as well analyzing the effects of ilvA and serA on soy sauce-like aroma. We employed quantitative descriptive sensory analysis (QDA), gas chromatography-olfactometry-mass spectrometry (GC-O-MS), relative odor activity value analysis (rOAV), principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), and partial least squares regression analysis (PLSR). QDA revealed the predominant soy sauce-like aroma profile of roasted and smoky aromas. GC-MS detected 99 volatile components, predominantly pyrazines and ketones, across the four samples, each showing varying concentrations. Based on rOAV (>1) and GC-O, 12 compounds emerged as primary contributors to soy sauce-like aroma. PCA and OPLS-DA were instrumental in discerning aroma differences among the samples, identifying five compounds with VIP > 1 as key marker compounds influencing soy sauce-like aroma intensity levels. Differential analyses of key aroma compounds indicated that the mutant strains of ilvA and serA affected soy sauce-like aroma mainly by affecting pyrazines. PLSR analysis indicated that roasted and smoky aromas were the two most important sensory attributes of soy sauce-like aroma, with pyrazines associated with roasted aroma and guaiacol associated with smoky aroma. In addition, substances positively correlated with the intensity of soy sauce-like aroma were verified by additional experiments. This study enhances our understanding of the characteristic flavor compounds in soy sauce-like aroma ferments, provides new perspectives for analyzing the molecular mechanisms of soy sauce-like aroma formation, and provides a theoretical framework for the targeted enhancement of soy sauce-like aroma in various foods.

Hepatitis B virus (HBV) expresses co-terminal large (L), middle (M), and small (S) envelope proteins containing preS1/preS2/S, preS2/S, and S domain alone, respectively. S and preS1 domains mediate sequential virion attachment to heparan sulfate proteoglycans and sodium taurocholate cotransporting polypeptide (NTCP), respectively, which can be blocked by anti-S and anti-preS1 antibodies. How anti-preS2 antibodies neutralize HBV infectivity remains enigmatic. The late stage of chronic HBV infection often selects for mutated preS2 translation initiation codon to prevent M protein expression, or in-frame preS2 deletions to shorten both L and M proteins. When introduced to infectious clone of genotype C or D, both M-minus mutations and most 5' preS2 deletions sustained virion production. Such mutant progeny viral particles were infectious in NTCP-reconstituted HepG2 cells. Neutralization experiments were performed on the genotype D clone. Although remaining susceptible to anti-preS1 and anti-S neutralizing antibodies, M-minus mutants were only partially neutralized by two anti-preS2 antibodies tested while preS2 deletion mutants were resistant. By infection experiments using viral particles with lost versus increased M protein expression, or a neutralization escaping preS2 deletion only present on L or M protein, we found that both full-length L and M proteins contributed to virus neutralization by the two anti-preS2 antibodies. Thus, immune escape could be a driving force for the selection of M-minus mutations, and especially preS2 deletions. The fact that both L and M proteins could mediate neutralization by anti-preS2 antibodies may shed light on the underlying molecular mechanism.IMPORTANCEThe large (L), middle (M), and small (S) envelope proteins of hepatitis B virus (HBV) contain preS1/preS2/S, preS2/S, and S domain alone, respectively. The discovery of heparan sulfate proteoglycans and sodium taurocholate cotransporting polypeptide (NTCP) as the low- and high-affinity HBV receptors could explain neutralizing potential of anti-S and anti-preS1 antibodies, respectively, but how anti-preS2 neutralizing antibodies work remains enigmatic. In this study, we found two M-minus mutants in the context of genotype D partially escaped two anti-preS2 neutralizing antibodies in NTCP-reconstituted HepG2 cells, while several naturally occurring preS2 deletion mutants escaped both antibodies. By point mutations to eliminate or enhance M protein expression, and by introducing preS2 deletion selectively to L or M protein, we found binding of anti-preS2 antibodies to both L and M proteins contributed to neutralization of wild-type HBV infectivity. Our finding may shed light on the possible mechanism(s) whereby anti-preS2 antibodies neutralize HBV infectivity., Competing Interests: The authors declare no conflict of interest.

Conventional drug delivery techniques face challenges related to targeting and adverse reactions. Recent years have witnessed significant advancements in nanoparticle-based drug carriers. Nevertheless, concerns persist regarding their safety and insufficient metabolism. Employing cells and their derivatives, such as cell membranes and extracellular vesicles (EVs), as drug carriers effectively addresses the challenges associated with nanoparticle carriers. However, an essential hurdle remains in efficiently loading drugs into these carriers. With the advancement of microfluidic technology and its advantages in precise manipulation at the micro- and nanoscales, as well as minimal sample loss, it has found extensive application in the loading of drugs using cells and their derivatives, thereby fostering the development of drug-loading techniques. This paper outlines the characteristics and benefits of utilizing cells and their derivatives as drug carriers and provides an overview of current drug-loading techniques, particularly those rooted in microfluidic technology. The significant potential for microfluidic technology in targeted disease therapy through drug delivery systems employing cells and their derivatives, is foreseen., (© 2024 Wiley‐VCH GmbH.)

Arsenic (As) has been classified as a carcinogen for humans. There is abundant evidence indicating that arsenic increases the risk of bladder cancer among human populations. However, the underlying mechanisms have yet to be fully understood and elucidated. NADPH oxidases (NOXs) are the main enzymes for ROS production in the body. NADPH Oxidase 2 (NOX2), which is the most distinctive and ubiquitously expressed subunit of NOXs, can promote the formation and development of tumors. The utilization of NOX2 as a therapeutic target has been proposed to modulate diseases resulting from the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Matrine has been reported to exhibit various pharmacological effects, including anti-inflammatory, antifibrotic, antitumor, and analgesic properties. However, it has not been reported whether matrine can inhibit malignant transformation induced by arsenic in uroepithelial cells through NOX2. We have conducted a series of experiments using both a sub-chronic NaAsO 2 exposure rat model and a long-term NaAsO 2 exposure cell model. Our findings indicate that arsenic significantly increases cell proliferation, migration, and angiogenesis in vivo and in vitro. Arsenic exposure resulted in an upregulation of reactive oxygen species (ROS), NOX2, and NLRP3 inflammasome expression. Remarkably, both in vivo and in vitro, the administration of matrine demonstrated a significant improvement in the detrimental impact of arsenic on bladder epithelial cells. This was evidenced by the downregulation of proliferation, migration, and angiogenesis, as well as the expression of the NOX2 and NLRP3 inflammasomes. Collectively, these findings indicate that matrine possesses the ability to reduce NOX2 levels and inhibit the transformation of bladder epithelial cells.

Background: Irritable bowel syndrome (IBS) significantly impacts individuals due to its prevalence and negative effect on quality of life. Current genome-wide association studies (GWAS) have only identified a small number of crucial single nucleotide polymorphisms (SNPs), not fully elucidating IBS's pathogenesis., Objective: To identify genomic loci at which common genetic variation influence IBS susceptibility., Methods: Combining independent cohorts that in total comprise 65,840 cases of IBS and 788,652 controls, we performed a meta-analysis of genome-wide association studies (GWAS) of IBS. We also carried out gene mapping and pathway enrichment to gain insights into the underlying genes and pathways through which the associated loci contribute to disease susceptibility. Furthermore, we performed transcriptome analysis to deepen our understanding. IBS risk models were developed by combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. We detect the phenotype association for IBS utilizing PRS-based phenome-wide association (PheWAS) analyses, linkage disequilibrium score regression, and Mendelian randomization., Results: The GWAS meta-analysis identified 10 IBS risk loci, seven of which were novel (rs12755507, rs34209273, rs34365748, rs67427799, rs2587363, rs13321176, rs1546559). Multiple methods identified nine promising IBS candidate gene (PRRC2A, COP1, CADM2, LRP1B, SUGT1, MED12L, P2RY14, PHF2, SHISA6) at 10 GWAS loci. Transcriptome validation also revealed differential expression of these genes. Phenome-wide associations between PRS-IBS and nine traits (neuroticism, diaphragmatic hernia, asthma, diverticulosis, cholelithiasis, depression, insomnia, COPD, and BMI) were identified. The six diseases (asthma, diaphragmatic hernia, diverticulosis, insomnia major depressive disorder and neuroticism) were found to show genetic association with IBS and only major depressive disorder and neuroticism were found to show causality with IBS., Conclusion: We identified seven novel risk loci for IBS and highlight the substantial influence on genetic risk harboured. Our findings offer novel insights into aetiology and phenotypic association of IBS and lay the foundation for therapeutic targets and interventional strategies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The emissions of sulfur dioxide (SO 2 ) from combustion exhaust gases pose significant risks to public health and the environment due to their harmful effects. Therefore, the development of highly efficient adsorbent polymers capable of capturing SO 2 with high capacity and selectivity has emerged as a critical challenge in recent years. However, existing polymers often exhibit poor SO 2 /CO 2 and SO 2 /N 2 selectivity. Herein, we report two triazine-functionalized triphenylamine-based nanoporous organic polymers (ANOP-6 and ANOP-7) that demonstrate both good SO 2 uptake and high SO 2 /CO 2 and SO 2 /N 2 selectivity. These polymers were synthesized through cost-effective Friedel-Crafts reactions using cyanuric chloride, 3,6-diphenylaminecarbazole, and 2,2',7,7'-tetrakis(diphenylamino)-9,9'-spirobifluorene. The resultant ANOPs are composed of triazine and triphenylamine units and feature an ultramicroporous structure. Remarkably, ANOPs exhibit impressive adsorption capacities for SO 2 , with uptakes of approximately 3.31-3.72 mmol·g -1 at 0.1 bar, increasing to 9.52-9.94 mmol·g -1 at 1 bar. The static adsorption isotherms effectively illustrate the ability of ANOPs to separate SO 2 from SO 2 /CO 2 and SO 2 /N 2 mixtures. At 298 K and 1 bar, ANOP-6 shows outstanding selectivity toward SO 2 /CO 2 (248) and SO 2 /N 2 (13146), surpassing all previously reported triazine-based nanoporous organic polymers. Additionally, dynamic breakthrough tests demonstrate the superior separation properties of ANOPs for SO 2 from an SO 2 /CO 2 /N 2 mixture. ANOPs exhibit a breakthrough time of 73.1 min·g -1 and a saturated SO 2 capacity of 0.53 mmol·g -1 . These results highlight the exceptional adsorption properties of ANOPs for SO 2 , indicating their promising potential for the highly efficient capture of SO 2 from flue gas.

G9a, which was initially identified as a histone H3 Lys9 (H3K9) methyltransferase, is potentially an attractive therapeutic target for human cancers. Despite its importance, there is no available selective G9a chemical probe because its homologous protein GLP shares approximately 80% of its sequence with G9a. The development of G9a chemical probes with high selectivity for G9a over GLP is a big challenge but is extremely valuable for understanding G9a-related biology. Herein, we developed a first-in-class selective G9a degrader G9D-4 , which induced a dose- and time-dependent G9a degradation without degradation of GLP. G9D-4 exhibited effective antiproliferative activities in a panel of pancreatic cancer cell lines and was able to sensitize KRAS G12D mutant pancreatic cancer cells to KRAS G12D inhibitor MRTX1133. These data clearly demonstrated the practicality and importance of a selective G9a degrader as a preliminary chemical probe suitable for understanding G9a-related biology and a promising strategy for the treatment of pancreatic cancer.

In recent years, using pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H 2 O 2 ) production in solid tumors. The H 2 O 2 is then converted into cytotoxic hydroxyl free radicals (HO˙) by redox-active Fe 2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conversion of H 2 O 2 to HO˙ by wüstite (Fe 1- x O) nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H 2 O 2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.

Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR., Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites., Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%)., Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro / in vivo diagnostic strategies to ascertain drug causality., Trial Registration: ANZCTR ACTRN12619000241134. Registered 19 February 2019., Competing Interests: No relevant conflicts of interest to declare., (© 2024 The Author(s).)