Ferroptosis Contributes to Isoflurane Neurotoxicity

The underlying mechanisms of isoflurane neurotoxicity in the developing brain remain unclear. Ferroptosis is a recently characterized form of programmed cell death distinct from apoptosis or autophagy, characterized by iron-dependent reactive oxygen species (ROS) generation secondary to failure of glutathione-dependent antioxidant defenses. The results of the present study are the first to demonstrate in vitro that ferroptosis is a central mechanism contributing to isoflurane neurotoxicity. We observed in embryonic mouse primary cortical neuronal cultures (day-in-vitro 7) that 6 h of 2% isoflurane exposure was associated with decreased transcription and protein expression of the lipid repair enzyme glutathione peroxidase 4. In parallel, isoflurane exposure resulted in increased ROS generation, disruption in mitochondrial membrane potential, and cell death. These effects were significantly attenuated by pre-treatment with the selective ferroptosis inhibitor ferrostatin-1 (Fer-1). Collectively, these observations provide a novel mechanism for isoflurane-induced injury in the developing brain and suggest that pre-treatment with Fer-1 may be a potential clinical intervention for neuroprotection

Anesthetic application of PetCO2 monitoring nasopharyngeal airway to magnifying endoscopy in patients with obstructive sleep apnea syndrome

Objective·To investigate the anesthetic effect of PetCO2 monitoring nasopharyngeal airway on preventing hypoxia in patients with obstructive sleep apnea syndrome (OSAS) during magnifying endoscopy.Methods·Eighty OSAS patients who underwent magnifying endoscopy anesthesia in Xuchang Central Hospital of Henan Province from February to June 2023 were randomly divided into PetCO2 monitoring nasopharyngeal airway group (group T) and traditional nasopharyngeal airway group (group B), with 40 cases in each group. General information, perioperative data and total anesthetic dosage of the two groups of patients were collected and compared. The systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and pulse oxygen saturation (SpO2) of the two groups of patients before anesthesia (T0), at the time of entering the endoscopy (T1), 3 min after entering the endoscopy (T2), 10 min after entering the endoscopy (T3) and at the end of endoscopy (T4) were observed and recorded, respectively. The incidence of body movement and hypoxemia, and the effects of preventing hypoxia (including mask ventilation, jaw-lift support and chest compressions to assist breath) of the two groups of patients were recorded.Results·There were no significant differences in general information, perioperative data and total anesthetic dosage between the two groups. At T1 and T2, SpO2 in group T was higher than that in group B (T1: P=0.041,T2: P=0.012), and there was no statistically significant difference in SBP, DBP and HR between the groups; at other time points, there was no statistically significant difference in the four indicators between the two groups. Compared with group B, the incidences of body movement, hypoxemia, mask ventilation, jaw-lift support and chest compressions to assist breath in group T were all decreased (all P=0.000).Conclusion·PetCO2 monitoring nasopharyngeal airway can reduce the incidence of hypoxia during magnifying endoscopy in patients with OSAS, with minimal adverse events. Also, it can detect the status of lung ventilation in time, guide clinical intervention, reduce complications and improve the safety of magnifying endoscopy anesthesia

Association analysis between the TLR9 gene polymorphism rs352140 and type 1 diabetes

BackgroundTo a great extent, genetic factors contribute to the susceptibility to type 1 diabetes (T1D) development, and by triggering immune imbalance, Toll-like receptor (TLR) 9 is involved in the development of T1D. However, there is a lack of evidence supporting a genetic association between polymorphisms in the TLR9 gene and T1D.MethodsIn total, 1513 individuals, including T1D patients (n=738) and healthy control individuals (n=775), from the Han Chinese population were recruited for an association analysis of the rs352140 polymorphism of the TLR9 gene and T1D. rs352140 was genotyped by MassARRAY. The allele and genotype distributions of rs352140 in the T1D and healthy groups and those in different T1D subgroups were analyzed by the chi-squared test and binary logistic regression model. The chi-square test and Kruskal−Wallis H test were performed to explore the association between genotype and phenotype in T1D patients.ResultsThe allele and genotype distributions of rs352140 were significantly different in T1D patients and healthy control individuals (p=0.019, p=0.035). Specifically, the T allele and TT genotype of rs352140 conferred a higher risk of T1D (OR=1.194, 95% CI=1.029-1.385, p=0.019, OR=1.535, 95% CI=1.108-2.126, p=0.010). The allele and genotype distributions of rs352140 were not significantly different between childhood-onset and adult-onset T1D and between T1D with a single islet autoantibody and T1D with multiple islet autoantibodies (p=0.603, p=0.743). rs352140 was associated with T1D susceptibility according to the recessive and additive models (p=0.015, p=0.019) but was not associated with T1D susceptibility in the dominant and overdominant models (p=0.117, p=0.928). Moreover, genotype-phenotype association analysis showed that the TT genotype of rs352140 was associated with higher fasting C-peptide levels (p=0.017).ConclusionIn the Han Chinese population, the TLR9 polymorphism rs352140 is associated with T1D and is a risk factor for susceptibility to T1D

Targeting the metabolic profile of amino acids to identify the key metabolic characteristics in cerebral palsy

BackgroundCerebral palsy (CP) is a neurodevelopmental disorder characterized by motor impairment. In this study, we aimed to describe the characteristics of amino acids (AA) in the plasma of children with CP and identify AA that could play a potential role in the auxiliary diagnosis and treatment of CP.MethodsUsing high performance liquid chromatography, we performed metabolomics analysis of AA in plasma from 62 CP children and 60 healthy controls. Univariate and multivariate analyses were then applied to characterize different AA. AA markers associated with CP were then identified by machine learning based on the Lasso regression model for the validation of intra-sample interactions. Next, we calculated a discriminant formula and generated a receiver operating characteristic (ROC) curve based on the marker combination in the discriminant diagnostic model.ResultsA total of 33 AA were detected in the plasma of CP children and controls. Compared with controls, 5, 7, and 10 different AA were identified in total participants, premature infants, and full-term infants, respectively. Of these, β-amino-isobutyric acid [p = 2.9*10(−4), Fold change (FC) = 0.76, Variable importance of protection (VIP) = 1.75], tryptophan [p = 5.4*10(−4), FC = 0.87, VIP = 2.22], and asparagine [p = 3.6*10(−3), FC = 0.82, VIP = 1.64], were significantly lower in the three groups of CP patients than that in controls. The combination of β-amino-isobutyric acid, tryptophan, and taurine, provided high levels of diagnostic classification and risk prediction efficacy for preterm children with an area under the curve (AUC) value of 0.8741 [95% confidence interval (CI): 0.7322–1.000]. The discriminant diagnostic formula for preterm infant with CP based on the potential marker combination was defined by p = 1/(1 + e−(8.295–0.3848* BAIBA-0.1120*Trp + 0.0108*Tau)).ConclusionFull-spectrum analysis of amino acid metabolomics revealed a distinct profile in CP, including reductions in the levels of β-amino-isobutyric acid, tryptophan, and taurine. Our findings shed new light on the pathogenesis and diagnosis of premature infants with CP

SegRap2023: A Benchmark of Organs-at-Risk and Gross Tumor Volume Segmentation for Radiotherapy Planning of Nasopharyngeal Carcinoma

Radiation therapy is a primary and effective NasoPharyngeal Carcinoma (NPC) treatment strategy. The precise delineation of Gross Tumor Volumes (GTVs) and Organs-At-Risk (OARs) is crucial in radiation treatment, directly impacting patient prognosis. Previously, the delineation of GTVs and OARs was performed by experienced radiation oncologists. Recently, deep learning has achieved promising results in many medical image segmentation tasks. However, for NPC OARs and GTVs segmentation, few public datasets are available for model development and evaluation. To alleviate this problem, the SegRap2023 challenge was organized in conjunction with MICCAI2023 and presented a large-scale benchmark for OAR and GTV segmentation with 400 Computed Tomography (CT) scans from 200 NPC patients, each with a pair of pre-aligned non-contrast and contrast-enhanced CT scans. The challenge's goal was to segment 45 OARs and 2 GTVs from the paired CT scans. In this paper, we detail the challenge and analyze the solutions of all participants. The average Dice similarity coefficient scores for all submissions ranged from 76.68\% to 86.70\%, and 70.42\% to 73.44\% for OARs and GTVs, respectively. We conclude that the segmentation of large-size OARs is well-addressed, and more efforts are needed for GTVs and small-size or thin-structure OARs. The benchmark will remain publicly available here: https://segrap2023.grand-challenge.orgComment: A challenge report of SegRap2023 (organized in conjunction with MICCAI2023

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

The Green and Adaptable Development Paths of Provincial Characteristic Towns in Taihu Lake Basin: A Synergy Perspective on Face Value and Resilience

Enhancing the synergistic development level of face value and resilience is the key to achieving green and high-quality development of characteristic towns. This study takes 83 characteristic towns in Taihu Lake Basin as research samples, constructs a systematic evaluation index system of the face value and resilience, and scientifically classifies the face value and resilience of Taihu Lake Basin into high level, medium–high level, medium level, and low level, respectively, and explores the intrinsic influence mechanism of the deviation between the face value and resilience via the deviation index and synergy development degree model. The results show that (1) the face value of about 60% of the characteristic towns is above average, which is distributed in the northern and southeast regions of Taihu Lake Basin. In terms of the industry type, the face value level of characteristic towns of tourism, digital economy, information, and finance is high. (2) The number of characteristic towns with moderate resilience is the largest, accounting for 36.1%. Spatially, the characteristic towns with medium–high and high levels are mainly concentrated in Hangzhou, Kunshan, Wuxi, and Shanghai. In terms of the industry type, the resilience levels of tourism towns, digital economy towns, and modern service towns with distinctive industrial characteristics are higher. (3) The face value and resilience of most characteristic towns in Taihu Lake Basin are not synchronized, and 67.5% of the towns have a large deviation. We classify 83 characteristic towns into four categories: high robustness (Hj > 4.80), medium–high robustness (4.02 ≤ Hj ≥ 4.79), medium robustness (4.03 ≤ Hj ≥ 3.11), and low robustness (Hj < 3.10); the high robustness areas are concentrated in Suzhou–Wuxi–Changzhou and the northern part of Zhejiang. (4) We propose the differentiated development paths of synergistic development between face value and resilience, and the synergistic cooperation and governance mechanism of multiple subjects for the achievement of balanced development in characteristic towns. The conclusions of this study have important research value and practical significance for the sustainable development of similar characteristic towns

Complete mitochondrial genome sequence for the black croaker Atrobucca nibe (Perciformes, Sciaenidae) and its phylogeny

The blackmouth croaker, Atrobucca nibe (Jordan & Thompson, 1911), is one of the most important economic fish in China. The mitogenome of A. nibe was determined in this study. The full circle length of the complete mitochondrial DNA was 16,505 bp. It contained 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a control region (D-loop). All 21 tRNA genes can fold into a typical cloverleaf structure except for tRNASer (AGY). The phylogenetic analysis revealed that A. nibe clustered into the three species of Sciaenidae (Pennahia microcephalus, Chrysochi aureus and Protonibea diacanthus)