Rabi 2018–2019 and 2019–20 to find out the influence of different residue and weed management practices on weed dynamics, growth, yield, energetics, carbon footprint, economics and soil properties in zero-tilled sown wheat at Research Farm, AICRP-Weed management, SKUAST-Jammu. The experiment with four rice residue management practices and four weed management practices was conducted in a Strip-Plot Design and replicated thrice. The results showed that residue retention treatments recorded lower weed density, biomass and higher wheat growth, yield attributes and yields of wheat as compared to no residue treatment. The magnitude of increase in wheat grain yield was 17.55, 16.98 and 7.41% when treated with 125% recommended dose of nitrogen + residue + waste decomposer (RDN + R + WD), 125% RDN + R, and 100% RDN + R, respectively, compared to no residue treatment. Further, all three herbicidal treatments decreased weed density and biomass than weedy treatments. Consequently, a reduction of 29.30, 28.00, and 25.70% in grain yield were observed in control as compared to sulfosulfuron + carfentrazone, clodinafop-propargyl + metasulfuron, and clodinafop-propargyl + metribuzin, respectively. Moreover, 125% RDN + R + WD obtained significantly higher energy output (137860 MJ ha−1) and carbon output (4522 kg CE/ha), but 100% RDN had significantly higher net energy (101802 MJ ha−1), energy use efficiency (7.66), energy productivity (0.23 kg MJ−1), energy profitability (6.66 kg MJ−1), carbon efficiency (7.66), and less carbon footprint (7.66) as compared to other treatments. Despite this, treatments with 125% RDN + R + WD and 125% RDN + R provided 17.58 and 16.96% higher gross returns, and 24.45% and 23.17% net outcomes, respectively, than that of control. However, compared to the control, sulfosulfuron + carfentrazone showed considerably higher energy output (140492 MJ ha−1), net energy (104778 MJ ha−1), energy usage efficiency (4.70), energy productivity (0.14 kg MJ−1), energy profitability (3.70 kg MJ−1), carbon output (4624 kg CE ha−1), carbon efficiency (4.71), and lower carbon footprint (0.27). Furthermore, sulfosulfuron + carfentrazone, clodinafop-propargyl + metasulfuron, and clodinafop-propargyl + metribuzin recorded 29.29% and 38.42%, 27.99%, and 36.91%, 25.69% and 34.32% higher gross returns and net returns over control treatment, respectively. All three herbicides showed higher gross returns, net returns, and benefit cost ratio over control. The soil nutrient status was not significantly affected either by residue or weed management practices. Therefore, based on present study it can be concluded that rice residue retention with 25% additional nitrogen and weed management by clodinafop-propargyl + metasulfuron herbicide found suitable for zero tillage wheat.A two-year field study was conducted during  It contributed about 760 million tonnes to the global food grain basket in the year 2020–2021, from an area of about 219.70 million hectares. World-wide India is firmly occupying the second position among the wheat producing countries after China, while in India, this crop occupies about 30.79 million hectares area and accounts for production of about 107.59 million tonnes with productivity of 3494 kg ha−11. Weeds are usually a threat to wheat growth and productivity due to the competition for nutrients, water, light, and space. However, heavy infestation of weeds is one of the foremost constraints to the sustainable production under zero-tillage sown wheat. If do not interfere with weeds growth, it may reduce wheat yield by 15 to 40% depending upon the magnitude, nature, and duration of weed2. Farmers have recently been burning significant amounts of crop residues that were left in the field after mechanized harvesting, which interfere with tillage and following operations for the future crop and result in the loss of nutrients and soil organic matter (SOM). Retaining residue on the field improves soil health, soil water conservation, soil productivity, and the environment. However, incorporating residue presents a number of difficulties, including labor-intensiveness, fallow periods, and N immobilization. Therefore, after complete removal of all loose residue from the field, wheat was sown with a zero-tilled seed cum fertilizer drill on sanding rice residue (30–35 cm height) to guarantee timely sowing, avoid extensive tillage operation, and make the best use of available resources under the current scenario.Wheat Phalaris minor in wheat. The transition from an intense tillage system to a reduced/no-tillage system results in significant changes in weed dynamics, pesticide effectiveness, and weed seed recruitment4. The present weed control enormously focuses on chemical weed measures. Thus, extensive use of herbicides quickly leads to herbicide resistance in weeds, which is a serious environmental issue and is a matter of concern. Therefore, it’s time to modify weed control approaches to manage the population below the competition threshold level to prevent the problem of herbicide resistance in weeds and increase wheat production in zero-till systems. Agronomic intervention in arable fields can influence weed flora, weed community species composition, and soil seed bank5. Consequently, crop rotation, fertilization, tillage, and residue retention are effective measures for controlling weeds. Further, weed management varies amongst different tillage systems, with small seed species favored by conservation tillage systems for the composition of weed community changes, thus requiring different weed control strategies6. In addition, weed germination is generally reduced in conservation tillage systems over conventional tillage systems due to less disturbance of soil7. As a result, if weeds can be well managed in the early years of conservation tillage, the weed seed bank will be reduced, and ultimately, the potential for high infestation of weeds derived from seeds will decrease8.Adopting no or reduced tillage is a potential alternative for mitigating the difficulties caused by intense tillage in rice and delayed wheat sowing. Zero tillage alleviates the problem of delayed planting while also reducing weeds such as 9. Tillage strongly influences the number and diversity of weed seed banks and has an overriding influence on weed shift.However, zero tillage can advance the sowing time as the crop can be sown without any field preparation through a single tractor operation using a specially designed seed-cum-fertilizer drill. Therefore, zero tillage is divisible and flexible in operation, allowing farmers to gain more than in a driving situation. Tillage affects weed infestation. Hence, interactions between tillage and weed management measures are widespread in crop production. Thus, zero tillage prevents weed emergence and creates a more suitable atmosphere for early crop establishment10. Further, residue retention on the surface or as mulch proves to result in lower weed density and biomass in broad-leaved as well as narrow-leaved weeds. Additionally, long-term field studies involving the use of rice residue as a component of integrated weed management strategies need to be conducted in the rice–wheat cropping system. Because, rice residue has the potential to sustainably manage the weeds at a low cost. Therefore, the combined adoption of multiple weed control options, both chemical and nonchemical practices such as residue management (retention or incorporation), can help in the effective management of weeds in wheat. Various rice residue management strategies have a variable effect on weed dynamics in wheat due to either physical hindrance or allelopathic interactions. Therefore, the main objective of present study was studying the impact of nitrogen dose, rice residue and chimerical weed management options for controlling weed infestation, energetics, carbon footprint, and economic in zero tillage wheat.On other hand, crop residue management is another effective agronomic strategy for weed control because it reduces the amount of sunlight entering the soil surface and provides a safe harbor for bacteria, fungus, insects, and other predatorsRabi seasons of 2018–2019 and 2019–2020 in Research Farm of All India Cordinated Research Project on Weed Management, SKUAST-Jammu, Chatha located in the Shiwalik foothills of the North-Western Himalayas, situated at 32° 40' N latitude and 74° 58'E longitude with an altitude of 332 m above mean sea level. The meteorological data with respect to rainfall, temperature and relative humidity were recorded from the meteorological observatory located very close to the experimental area which reveals that the experimental site was mainly sub-tropical in nature endowed with hot and dry summers followed by hot and humid monsoon seasons. The mean annual rainfall of the location varied from 1050–1115 mm of which about 75 per cent was received from June to September. The soil of the experimental field was sandy clay loam in texture, slightly alkaline in reaction, low in organic carbon and available nitrogen but medium in phosphorus and potassium.The present experiment was carried out during Four rice residue management practices namely 100% recommended dose of nitrogen (RDN) + rice residue (R), 125% RDN + R, 125% RDN + R + waste decomposer (WD) and 100% RDN without residue (R) and four weed management practices namely sulfosulfuron + carfentrazone (25 + 20 g/ha), clodinafop-propargyl + metsulfuron (60 + 4 g/ha), clodinafop-propargyl + metribuzin (54 + 120 g/ha) and control were established in a Strip-Plot Design replicated thrice. The dimension of gross and net plot was 6 m × 4.4 m and 5 m × 3.4 m, respectively.−1. The crop was irrigated twice during 1st and 2nd year the experiment due to evenly distribution of rainfall. The crop was fertilized with 50: 25 kg of P2O5 and K2O ha−1, respectively. While, nitrogen was applied as per treatments (100% RDN means 100 kg N/ha). Full doses of phosphorus and potassium along with one-third of nitrogen were applied as basal doses at the time of sowing. The remaining half quantity of nitrogen was applied in two equal splits—at crown root initiation stage and just before ear initiation stage.In standing rice plots, direct seeded rice was harvested with combine harvester at a particular height of 30–35 cm above ground and loose residue was completely removed from the field. However, in no residue plots, both loose and standing residue was removed completely from the field. Wheat variety “HD 3086” was used for the study. The seeds were sown with zero till seed cum drill on 17th November 2018 and 16th November 2019. The amount of seed rate was 125 kg ha−1 as per technical programme.Organic waste decomposer (WD) solution was prepared and spayed on standing rice residue in the field. For preparation of waste decomposer for 1 ha area used material was 100 ml decomposer, 1 kg besan (chickpea flour), 2.5 kg Jaggery and 200 letter waters. We added 1 kg besan and 2.5 kg jaggery in 200 letter water and mixed it properly and after that added 100 ml of decomposer and kept for 15 days to get ready for use in the field. After 15 days waste decomposer was applied on standing rice residue after sowing of wheat at the rate of 500 letter ha−1. Control plot was maintained herbicide free during both the experimental years.As per technical programme which mentioned in above section all herbicidal treatments were applied at 30–35 DAS using Knapsack sprayer fitted with flat fan nozzles with 500 letter water haThe information on the parameters of wheat growth, including plant height (cm), the number of tillers per square meter, and dry matter, was collected 60 days after sowing (DAS) and at harvest. The number of spikes per square meter of the wheat crop was measured before harvest. The average of ten spikes was used to calculate the number of grains per spike. From the net plot area, 1000 seeds were counted and their weight was determined and expressed as 1000-grain weight. Harvested net plot area was left in the field to completely dry before being bundled, with each bundle's weight being recorded. After threshing, wheat grain weight was subtracted from biological yield to produce straw yield.11 was applied in order to get an accurate reading of the weed density in wheat. The weed density was recorded from a quadrant (0.5 × 0.5 m) chosen at random in each plot at two points at 30 day after sowing (DAS) and harvest and the results were represented as no. m−2. Because of the large variation on weed densities that existed among the treatment prior to statistical analysis, the data were transformed using the square root operator (√x + 1). In a similar manner, for the purpose of determining the dry biomass of weeds, the weeds that were collected from an area of 0.25 square metres in wheat were first dried in the sun for two to three days, and then they were oven dried at a temperature of 70 °C until their weight remained constant. Weed dry matter at harvest and was expressed as g m−2. The weed control efficiency was worked out based on Mishra and Mishra11 equation which is given below:The standard quadrant approach developed by Mishra and MishraWhere, Wdc = Weed dry weight in control plot (weedy check); Wdt = Weed dry weight in treated plot (treatment).12 and Mittal and Dhawan13.Both operational (direct) and non-operational (indirect) forms of energy are included in the inputs for the energy. In contrast, non-operational energy included things like seed, manure, and chemical fertilisers and pesticides. Operational energy included things such manual labour, fuel, and machinery and etc. The computation of energy consumption on the basis of energy was carried out using the primary data on a variety of inputs as well as management techniques. The quantity of energy that can be extracted from the product (grain and straw) was determined by multiplying the amount of production with the energy equivalent that corresponds to it. The energy use indices were calculated as per the procedure given by Devasenapathy et al.14 and West and Marland15. As individual pesticide and herbicide emission coefficients are not readily available, it was anticipated that emissions from manufacturing, shipping, warehousing, and spraying would be consistent within a given pesticide class. The total amount of carbon used and released during crop production was determined by adding up the carbon equivalent of all inputs and products.Carbon equivalent (CE) was estimated by multiplying the input  with its corresponding emission coefficient as given by Lal14.*Plant biomass contains on an average 44% carbon content as given by Lal16.The carbon footprint of crop production was calculated as per the methodologies given by Ma et alP < 0.05) were used for comparison of treatments. All the weed data were square root transformed prior to analysis to normalize the residuals.The effect of residue and weed management on weed density, biomass, wheat growth parameters, yield attributes, yields, energetics and carbon footprint were analysed. Analysis of variance of the above-mentioned parameters were performed in OPSTAT software and LSD test with 95% probability level  are given in Table The information on grassy, broad-leaved and total weed biomass  as compared to 100% RDN + R residue and 100% RDN but was statistically at par with 125% RDN + R. (Table −1), net energy , energy use efficiency (4.70), energy productivity (0.14) and energy profitability (3.70) which was followed by clodinafop-propargyl + metsulfuron and clodinafop-propargyl + metribuzin and the lest energy indices were recorded by control treatment . In weed control, water and fertilizer contributed 37.25% and 35.09%, respectively. 125% RDN + R + WD had significantly higher carbon input than control and 100% RDN + R but was found to be statistically equal to 125% RDN + R due to higher grain and biomass output. As no residue was used, 100% RDN had a much greater carbon efficiency (7.66) and a lower carbon footprint (0.15 kg CE kg−1 wheat), which is also in agreement with the findings of Zhanga et al.34. Sulfosulfuron + carfentrazone weed control has increased carbon output, efficiency, and footprint. This is due to higher grain and straw yields as a result of higher efficacy on controlling weeds.The largest overall carbon input was noticed in residue retention treatments with thick residue coverage. Crop residue includes 44% carbon input; hence 125% RDN + R + WD has a greater carbon input36. Additionally, due to fewer weed completion and higher yield components, sulfosulfuron + carfentrazone was shown to have a much higher cost of production, gross returns, net returns, and benefit cost ratio, followed by clodinafop-propargyl + metsulfuron and clodinafop + metribuzin. Heavy weed infestation may have drained resources and led to subpar agricultural production, explaining why economic indicators improved less under treatment.The data depicted in Table Based on two years research it concluded that all residue retention treatments noticed lower density and biomass of grassy and broad-leaved weeds than treatments with no residue. Nevertheless, 125% RDN + R + WD and 125% RDN + R recorded considerably higher growth parameters, yield components, grain yield and straw yield as compared to 100% RDN + R and 100% RDN without residue. In a similar vein, 125% RDN + R + WD recorded higher energy output, carbon output, gross returns, net returns, and the benefit cost ratio. Further 100% RDN without residue obtained significantly higher net energy, energy use efficiency, energy profitability, and energy productivity, as well as carbon efficiency, and lower carbon footprint in comparison to the other treatments, but it produced significantly lower levels of grain yield, straw yield, gross returns, and net returns in comparison to the other treatments. When it came to the effectiveness of herbicidal weed management measures, all three herbicides performed similar to each other, although they recorded meaningfully lower density and biomass in comparison to the control treatment. Among the herbicidal treatment, clodinafop-propargyl + metasulfuron showed significantly higher growth, yield, energy output, energy use efficiency, net energy, energy profitability, carbon output, and a less carbon footprint in comparison to the control, but it was statistically comparable to clodinafop + metribuzin and clodinafop-propargyl + metasulfuron.Therefore, based on present study it can be recommended that rice residue retention with 25% additional nitrogen and weed management by clodinafop-propargyl + metasulfuron herbicide found suitable for zero tillage wheat .Supplementary Information.


Switching to rIX‐FP prophylaxis at dosing intervals of up to 14 days in a hemophilia B pediatric patient decreased treatment burden by reducing the number of administrations and hospital visits, without affecting efficacy or treatment adherence. This is particularly important in contexts of limited mobility and overloaded healthcare services. Recombinant factor IX albumin fusion protein , an extended half‐life recombinant factor IX (EHL FIX), has shown good prophylactic efficacy in clinical trials of treatments administered up to every 21 days in adult patients, and up to every 14 days in selected pediatric patients with hemophilia B.Here we report a real‐world case of a pediatric hemophilia B patient who switched from standard rFIX , a standard half‐life FIX (SHL FIX), to rIX‐FP prophylaxis during the COVID‐19 pandemic.2F9 gene (1436A < T), FIX level was 2.7%, and the patient had no family history of bleeding diathesis.A 4‐year‐old patient previously diagnosed with moderate hemophilia B (FIX = 2.7 IU/dL) presented in May 2018 with spontaneous hemarthrosis in the left knee. The patient began prophylactic treatment with rFIX (40 IU/kg) twice weekly, as he met the criteria for prophylaxis instead of on‐demand treatment according to the international guideline's recommendations.A rFIX‐FP pharmacokinetic profile performed using WAPPS‐Hemo V.2.03 showed an extended half‐life for rFIX‐FP  and a prolonged activity time (15 days) to reach FIX levels of 5%. Given these results and the available published evidence,The clinical evaluation on day 120 of treatment showed no change in joint status. For this reason, the administration regimen was extended to 40 IU/kg every 10 days. On day 160 of treatment, the patient was diagnosed with asymptomatic COVID‐19 and self‐isolated at home for 14 days following the recommendations of the health authorities at that moment. During this period, treatment with rIX‐FP remained unchanged. After 200 days of treatment, a PK study confirmed trough levels of 6.9 IU/dL at 14 days postinfusion. Prophylactic treatment was subsequently extended to 70 IU/kg every 14 days, and the patient has presented no bleeds or complications to date. Joint evaluations, performed annually, gave a Hemophilia Joint Health Score (HJHS) and HEAD‐US score of 0, and no signs of joint disease were detected  products have half‐lives that are 3–6 times longer than standard half‐life (SHL) products and offer the possibility of fewer injections. rIX‐FP is approved for starting once‐weekly prophylaxis in adult and pediatric patients with hemophilia B. For patients ≥12 years, further extension of the treatment interval up to 14 days may also be considered, and up to 21 days for patients >18 years.Our case demonstrates that switching from prophylaxis with SHL FIX to EHL rIX‐FP at dosing intervals of up to 14 days is an optimal approach in pediatric hemophilia B patients. This is in line with recent real‐world data showing the benefits of this switch in adults and children with hemophilia B from different countries.Spanish Society of Thrombosis and Hemostasis) recommended against switching FIX products during the COVID‐19 pandemic, but this patient switched before the publication of these guidelines. Nevertheless, in view of our patient's outcome, the recommendations could perhaps be individualized depending on the clinical, geographic, pharmacokinetic, and/or sociosanitary context.We are aware that the SETH , and savings in school/working days (for the patient and the parents).The outcomes from this clinical case are in line with those recently observed in a similar pediatric hemophilia B patient from Spain.Bolívar Luis Díaz‐Jordán: Conceptualization; formal analysis; investigation; writing – review and editing. Tamara Cebanu: Formal analysis; investigation; writing – review and editing. Sara García Barcenilla: Formal analysis; investigation; writing – review and editing. Maria Teresa Álvarez‐Román: Conceptualization; formal analysis; investigation; writing – review and editing.This service was funded by CSL Behring.BLDJ has received honoraria for speaking engagements or funds for research from CSL Behring, Takeda, NovoNordisk, Roche, Daiichi‐Sankyo, Sobi, Fresenius, Leo Pharma, Abbvie, and Janssen. TC has no conflicts of interest to declare. SGB has received honoraria for speaking engagements from Roche, NovoNordisk, CSL Behring, Takeda, Sobi, Biomarin, Novartis, Bayer and Pfizer. MTAR has received honoraria for speaking engagements or consultancy, or funds for research from Takeda, Bayer, CSL Behring, Grifols, Novo Nordisk, Sobi, Octapharma, Roche, Amgen, Novartis, and Pfizer.Written informed consent was obtained from the patient's parents to publish this report in accordance with the journal's patient consent policy.


This study aimed to evaluate the association of triglyceride-glucose (TyG) index, an insulin resistance surrogate biomarker, with first stroke in a hypertensive population and to explore potential influencing factors.This study, a cohort study among a rural Chinese hypertensive population, utilized data from the China Stroke Primary Prevention Trial (CSPPT). The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Multivariate analysis using Cox proportional hazards models was conducted.P = 0.013). When Quartiles 3 and 4 were combined (≥ 8.8), the hazard ratio was 1.41 compared with combined Quartiles 1 and 2 (< 8.8). Similar findings were observed for the association of TyG index with ischemic stroke. Further, a joint effect of baseline TyG index and age on first stroke was found. Using the group with TyG < 8.8 and age < 60 years as a reference, the highest hazard ratio of stroke was found in the group with a higher TyG index and aged 60 or greater .A total of 7569 hypertensive patients were included in this study. When TyG index was assessed as quartiles, compared with the reference group (Quartile 1), the hazard ratio of stroke was 1.04 in Quartile 2, 1.43 in Quartile 3, and 1.45 in Quartile 4, with a significant trend test (In a hypertensive population, baseline TyG index was associated with a significantly higher risk of first stroke. In addition, age was a significant effect modifier for this association.The online version contains supplementary material available at 10.1186/s12933-023-02082-1. Insulin resistance (IR) is a common risk factor for stroke, and is also considered to be an important marker for other stroke risk factors such as diabetes and dyslipidemia, driving the onset and progression of stroke , 2. The To date, important knowledge gaps in the relationship between TyG index and stroke remain. First, although some studies have demonstrated that TyG index is associated with a higher risk of stroke , 7, no sThis study was a post-hoc analysis of the CSPPT. The methodology and primary outcomes of the CSPPT have been previously reported . In brieThis study utilized the patient population within the enalapril group of the CSPPT to analyze the relationship between baseline TyG index and first stroke.  The initial sample consisted of 7947 patients with hypertension from the Lianyungang Center, and after excluding those with missing baseline triglyceride and glucose data, a total of 7569 participants were included in this study  guideline . The parThe primary outcome was a first nonfatal or fatal stroke, excluding subarachnoid hemorrhage and silent stroke. All study outcomes were reviewed and adjudicated according to standard criteria by an independent Endpoint Adjudication Committee.Baseline serum fasting glucose, fasting lipid and homocysteine levels were measured using automatic clinical analyzers (Beckman Coulter) at the core laboratory of the National Clinical Research Center for Kidney Disease, Nanfang Hospital, Guangzhou, China. Baseline serum folate and vitamin B12 were measured by a commercial laboratory using a chemiluminescent immunoassay . Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. MTHFR C677T polymorphisms were detected on an ABI Prism 7900HT sequence detection system (Life Technologies) using the TaqMan assay.TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2].Means ± SD or medians (25th percentile–75th percentile) and proportions were calculated for population characteristics by median of TyG index. Multivariate analyses were performed using Cox proportional hazards models to assess hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between TyG index and total and ischemic stroke risk. Models were adjusted for age, sex, body mass index (BMI), systolic blood pressure, diastolic blood pressure, total homocysteine, vitamin B12, estimated glomerular filtration rate (eGFR), MTHFR C677T, smoking status, alcohol drinking and treatment blood pressure. TyG index was assessed as a continuous and categorical variable: quartiles 1 to 4 and quartiles 1–2 versus quartiles 3–4. Cumulative event rates were estimated using the Kaplan–Meier method for outcomes that occurred in each of the quartile groups of TyG index. The joint effect of TyG index and age with stroke risk was further examined.2), systolic blood pressure [< 165.3 (median) versus ≥ 165.3 mmHg], diastolic blood pressure [< 95.3 (median) versus ≥ 95.3 mmHg], estimated glomerular filtration rate [< 96.2 (median) versus ≥ 96.2 mL/min/1.73 m2], folate [< 7.3 (median) versus ≥ 7.3 ng/mL], homocysteine [< 12.4 (median) versus ≥ 12.4 μmol/L], vitamin B12 [< 371.0 (median) versus ≥ 371.0 pg/mL], MTHFR C677T polymorphisms (CC versus CT versus TT), smoking status (never smoker versus former smoker versus current smoker), and alcohol consumption (never drinker versus former drinker versus current drinker).Additional stratified analyses were also conducted. To assess the modifying effects on the association between TyG and first stroke, we tested for interaction with potential covariates using interaction modeling. These covariates included age (< 60 versus ≥ 60 years), sex , body mass index (< 24 versus ≥ 24 kg/mhttp://www.empowerstats.com) and R software, version 4.0.0 (http://www.R-project.org/), were used for all statistical analyses.A 2-tailed P < 0.05 was considered to be statistically significant in all analyses. EmpowerStats , the hazard ratio of stroke was 1.37 (95% CI 0.90–2.08) in Quartile 2 (8.5– < 8.8), 1.98 (95% CI 1.34–2.93) in Quartile 3 (8.8– < 9.2), and 2.06 (95% CI 1.37–3.09) in Quartile 4 (≥ 9.2), with a significant trend test (P < 0.001) .In 2008, Simental-Mendía et al. first proposed TyG index, a composite index consisting of triglyceride and fasting glucose levels . As a suThis study is the first to confirm that a higher baseline TyG index is associated with an increased risk of total stroke and ischemic stroke in a hypertensive population, and these results are generally consistent with the results of previous studies in non-hypertensive populations. More importantly, this study found for the first time that age significantly affects the stroke predictive value of TyG index: those patients aged 60 years or more with a higher TyG index had up to 2.15 times higher stroke risk compared to those under age 60. This may be related to long-term accumulated vascular damage in the older hypertensive population, highlighting the importance of large screenings in elderly populations (aged 60 years or older) with hypertension. In addition, this study additionally found a synergistic effect of homocysteine with TyG index. Previous evidence suggests that homocysteine induces insulin resistance and a diabetic phenotype by acting on the pro-insulin receptor through protein cysteine-homocysteinylation (C-Hcy) . The FraThe exact mechanism of the TyG-stroke relationship is unclear, but evidence indicates that the TyG index is associated with subclinical atherosclerosis –22: a hiAs a simple, inexpensive and effective alternative to IR, the TyG index is expected to provide more value in the field of stroke prevention in the future, especially as a stroke screening tool for large studies. Currently, stroke remains a serious global public health problem , and ideThere are still some limitations of this study. First, TyG index was calculated from a single blood test result at baseline, and the effect of fluctuations in blood glucose and triglyceride levels over time cannot be excluded. Second, although this study found that a TyG index above 8.8 was associated with a significantly higher risk of stroke, future studies are needed to determine the optimal cut point value. Third, other traditional IR indicators were not measured at baseline in this study, and their value for stroke prevention cannot be compared with that of the TyG index. Finally, the data for this study were from the Lianyungang center of the CSPPT study. The extrapolation of our findings may be restricted, and more studies in Chinese and foreign populations are needed to validate our results.This study within a Chinese population with hypertension validated that baseline TyG index was associated with a significantly increased risk of stroke and further identified a modifying effect of age and homocysteine. As a reliable, low-cost, alternative marker of IR that can be obtained by blood tests and simple calculations, the TyG index is suitable for large studies and screening purposes, and is expected to play an important role in the field of stroke prevention in the future.Additional file 1: Figure S1. Flowchart of the study. Table S1. Subgroup analyses on the association between triglyceride-glucose index and risk of total stroke. Table S2. The joint effect of baseline triglyceride-glucose index and homocysteine on the risk of total stroke. Table S3. Comparison of baseline characteristics between the included and excluded populations.


Perioperative cisplatin‐based chemotherapy decreases the risk of death over surgery alone and is a standard of care. Here, we examined perioperative chemotherapy indications for stage IB‐III non‐small cell lung cancer (NSCLC) patients according to lobe‐specific analysis.Resectable NSCLC patients with stage IB–III who received perioperative chemotherapy with and without radiotherapy after lung resection were identified from the SEER database. Propensity score matching (PSM) analysis was performed to reduce the inherent bias of retrospective studies. The Kaplan–Meier method and log‐rank tests were used to assess the differences in overall survival (OS).The study enrolled 23,844 patients before PSM. The perioperative chemotherapy group had better OS than the nonperioperative chemotherapy group in stage IB–III NSCLC patients before and after PSM. However, subgroup analysis according to stage demonstrated that perioperative chemotherapy did not markedly benefit patients with stage IB. Furthermore, lobar subgroup analysis did not show survival advantages in primary tumors located in either the right middle lobe in stages II and III NSCLC or the right lower lobe in stage III NSCLC.Lobe‐specific perioperative chemotherapy is recommended in NSCLC patients. For stage IB NSCLC, right middle lobe NSCLC from stage IB‐III and right lower lobe NSCLC from stage III, perioperative chemotherapy might not confer survival benefits. Several factors, such as stage, chemotherapy regimens, and histologic type, need to be considered in the selection of perioperative chemotherapy to maximize the survival benefits of NSCLC patients. However, tumor location, an important factor affecting the prognosis of NSCLC, is not included in decisions regarding chemotherapy. Because tumors in different lobes are associated with different prognoses after surgery, radiotherapy, and immunotherapy,22.1SEER data are available to eligible individuals from the National Cancer Institute (NCI) upon completion of a data use agreement. We completed a data use agreement to access the data reported in this manuscript. A data use agreement per NCI/SEER policies was signed in order to obtain approval to access deidentified SEER public‐use data through SEER*Stat.2.2Cases were extracted from the SEER database (SEER stat 8.2.9.2). The inclusion criteria were as follows2.3p < 0.05.Pearson's chi‐square tests were used to compare categorical variables. Overall survival (OS) was assessed using the Kaplan–Meier method and compared using the log‐rank test. The correlations between clinicopathological characteristics and OS were estimated by Cox proportional hazards regression models, and the hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated. To balance multiple characteristics in retrospective studies to approximate a random experiment, PSM was performed between the nonperioperative chemotherapy group and perioperative chemotherapy group in stage IB‐III patients. Statistical analyses and PSM were performed using SPSS . Statistical significance was considered at a two‐sided 33.1p < 0.001). There was no significant difference in sex between the two arms (p = 0.357) and white people accounted for 84% of the population. Lung adenocarcinoma (LUAD) was the predominant histology, accounting for 40.52% of the cohort. There were significant differences in the prevalence of LN metastases between patients who received perioperative chemotherapy and those treated with surgery alone (p < 0.001). Consistent with previous studies, the right upper lobe (RUL) was the most common tumor site, accounting for 32.16%, and the remaining tumors were located in the left upper lobe (LUL), right lower lobe (RLL), left lower lobe (LLL), and right middle lobe (RML). Resection consisted of lobectomy in 84.45% and sublobar resection in 15.55% of patients; resection combined with LN dissection (88.69%) was the main treatment.The patient characteristics are described in Table As shown in Table 3.2p < 0.001; Figure p < 0.001; Figure Patients who received perioperative chemotherapy had a significant better OS than those who received surgery alone (p = 0.690). The absolute improvement was 7.8% for RUL (p < 0.001), 6.1% for RLL (p = 0.001), 7.7% for LUL (p < 0.001), and 3.9% for LLL (p = 0.013).To further explore the benefit of perioperative chemotherapy, lobar subgroup analyses were performed. As shown in Figure 3.3p = 0.001; Figure p = 0.880; Figure Next, we performed survival analysis according to stage subclassification . A total of 11,174 patients with stage IB were enrolled in the study. Before PSM, there was an absolute improvement in 5‐year survival of 6% after perioperative chemotherapy compared with surgery alone , although the survival benefit was smaller in younger people than in older people.As shown in Figure 3.5p < 0.001 both; Figure p = 0.460; Figure Survival analyses according to histological type showed that LUSC and LUAD patients who received perioperative chemotherapy had a better OS (3.6p < 0.001) and 3% (p = 0.015).As shown in Figure 3.7p < 0.001), and a similar positive effect was observed in women (p < 0.001).The results of analysis of survival according to sex are shown in Figure 3.8To explore any potentially confounding factors related to OS, Cox regression analysis was performed. The HRs, p values, and 95% CIs are summarized in Table 4p = 0.120).p = 0.043). Several RCTs including IALT,Over the past two decades, perioperative chemotherapy has become a standard treatment for NSCLC, and it has benefited many early‐stage patients with resectable tumors.p = 0.940) and PFS  were not significantly different between treatment groups , whereas a positive effect of neoadjuvant chemotherapy on OS and PFS was revealed in the IIB/IIIA group . In addition, a meta‐analysisp = 0.007) and an absolute survival improvement at 5 years of 5% for all stages, which was similar to the survival benefit with adjuvant chemotherapy.Unlike adjuvant chemotherapy, neoadjuvant chemotherapy, the other part of perioperative chemotherapy, has not been evaluated extensively. There are no studies assessing the effect of neoadjuvant chemotherapy specifically in stage IB patients. In Scagliotti's study,This retrospective study showed that patients who received perioperative chemotherapy had a better OS than those who underwent surgery alone including lobectomy and sublobar resection. However, the survival benefit was not significant in patients with IB disease. These results are consistent with those of previous studies. In this study, the absolute improvement in 5‐year OS after PSM was 6.3%, which was higher than the improvement reported in other studies, including the LACE Collaborative Group study (5.4% for adjuvant chemotherapy) and NSCLC Meta‐analysis Collaborative Group study (5% for neoadjuvant chemotherapy).p < 0.001). Thus, lobe‐specific analysis was performed in this study to explore whether tumor location affects the prognosis of NSCLC after perioperative chemotherapy and to identify the population that could benefit from perioperative chemotherapy. Previous studies classify RML into upper and lower groups to determine the effect on prognosis by Cox analysis. In this study, we consider RML as a subgroup to analyze the survival difference between perioperative chemotherapy and surgery alone, and found that patients with RML tumors did not significantly benefit from perioperative chemotherapy regardless of stage (stage IB–III), which is the first time this result is reported. The outcome of RML was reported to be the worst among all locations of NSCLC, which makes it unique and worthy of more attention.Primary tumor location may affect the prognosis of NSCLC after surgery, radiotherapy, and immunotherapy.To the best of our knowledge, this study is the first to discuss the difference between perioperative chemotherapy and surgery alone for NSCLC in different lung lobes. The study had several limitations. Firstly, although PSM was performed, there are still some unavoidable biases. Secondly, the SEER database provided no information on the regime on chemotherapy, such as dose and scheme. These factors may also influence the effect of perioperative chemotherapy. In addition, preoperative and postoperative CT would bring about different outcome in the surgery‐oriented treatments owing to their different mechanisms; however, we could not further analyze separately because the SEER database did not provide the information, which is also one of the limitations of our study. Meanwhile, the patient number of certain subgroup is low, especially for RML, which may lead to an inaccurate conclusion, therefore, results in RML needed to be validated in a larger sample size cohort. Lastly, due to inability to distinguish between neoadjuvant and adjuvant populations, we were unable to validate our findings in these two populations separately.5During the past decades, detecting technology and treatment in lung cancer have been developing rapidly with the rapid developments of precision medicine. For example, targeted therapy can help those with specific gene mutation and gain a better prognosis. Biomarker, such as TMB, can distinguish patient who may benefit from PD‐1/PD‐L1 inhibitor treatment. And our study, which is still needed to be verified in a larger cohort, may also guide physicians to provide a precise perioperative treatment strategy in early‐stage NSCLC. In conclusion, we proposed a precise lobe‐specific perioperative chemotherapy. For stage IB NSCLC, right middle lobe NSCLC from stage IB‐III and right lower lobe NSCLC from stage III, perioperative chemotherapy might not confer survival benefits.Xi Lei: Conceptualization ; data curation ; resources ; software . Tong Li: Conceptualization ; data curation ; formal analysis ; funding acquisition ; investigation ; resources ; software ; supervision . Fuling Mao: Conceptualization ; data curation ; resources ; software . Fan Ren: Data curation ; formal analysis ; supervision ; writing – original draft . Quanying Tang: Data curation ; methodology ; software ; supervision ; validation . Weibo Cao: Resources ; software ; writing – original draft ; writing – review and editing . Lingling Zu: Methodology ; project administration ; resources ; supervision ; validation ; visualization . Song XU: Conceptualization ; data curation ; formal analysis ; funding acquisition ; investigation ; methodology ; project administration ; resources .The present study was funded by the National Natural Science Foundation of China (82172776), Tianjin Key Medical Discipline  Construction Project (TJYXZDXK‐061B), and Diversified Input Project of Tianjin National Natural Science Foundation (21JCYBJC01770).The authors declare that they have no conflicts of interest regarding the content or publication of this paper.SEER data are available to eligible individuals from the National Cancer Institute (NCI) upon completion of a data use agreement. We completed a data use agreement to access the data reported in this manuscript. A data use agreement per NCI/SEER policies was signed in order to obtain approval to access deidentified SEER public‐use data through SEER*Stat.Figure S1Click here for additional data file.Figure S2Click here for additional data file.Figure S3Click here for additional data file.Figure S4Click here for additional data file.Figure S5Click here for additional data file.Figure S6Click here for additional data file.Table S1Click here for additional data file.


To develop a deep learning radiomics of multiparametric magnetic resonance imaging (DLRMM)‐based model that incorporates preoperative and postoperative signatures for prediction of local tumor progression (LTP) after thermal ablation (TA) in hepatocellular carcinoma (HCC).n = 189] and two external test cohorts [ETCs]). DLRMM features were extracted from T1WI + C, T2WI, and DWI using ResNet18 model. An integrative model incorporating the DLRMM signature with clinicopathologic variables were further built to LTP risk stratification. The performance of these models were compared by areas under receiver operating characteristic curve (AUC) using DeLong test.From May 2017 to October 2021, 417 eligible patients with HCC were retrospectively enrolled from three hospitals . After integrating clinical variable, DLRMM model obtained significant improvement with AUC of 0.870–0.869 in three cohorts , which can provide the risk stratification for overall survival of HCC patients.A total of 1668 subsequences and 31,536 multiparametric MRI slice including T1WI, T2WI, and DWI were collected simultaneously. The DLRMM signatures were extracted from tumor and ablation zone, respectively. Ablative margin, multiple tumors, and tumor abutting major vessels were regarded as risk factors for LTP in clinical model. The AUC of DLRMM model were 0.864 in PC, 0.843 in ETC1, and 0.858 in ETC2, which was higher significantly than those in clinical model (The DLRMM model is essential to identify LTP risk of HCC patients who underwent TA and may potentially benefit personalized decision‐making. Findings: In this multicenter study that included 417 patients, a deep learning radiomics model was proposed, which achieved high prediction accuracy with AUC of 0.864‐0.858 across one training and two external testing cohorts, and realized successful patient stratification of high and low local recurrence risk. Meaning: The proposed prediction system may help physicians in therapeutic decision making and surveillance strategy selection for hepatocellular carcinoma patients after thermal ablation in clinical practice. Accumulated evidence demonstrates that untreated micrometastases from the primary tumor, the subsequent spread along intrasegmental branches and vascular invasion may contribute to LTP. Although, numerous studies have suggest that LTP is associated with tumor aggressiveness, mainly including >5 cm of tumor diameter, microscopic vascular invasion, poor pathological differentiation, etc., it remains be not consistent owing to tumor heterogeneity and patients' individual differences.Accurate measurement of AM is extremely difficult, which is closely related to image registration before and after ablation. In view of the liver elastic deformation caused by respiratory movement and heat, it is difficult for radiologists to obtain accurate AM. To date, a well‐received biomarker for prediction remains elusive. Recently, the potential power of medical image data is recognized increasingly in the field of oncology.2This multiinstitutional study protocol was approved by the Ethics Committee of all participating institutions and conducted following the principles of the 1975 Declaration of Helsinki. The requirement for written informed consent was waived because of the retrospective nature of this study.2.1From May 2017 to October 2021, a total of 756 patients with early‐stage HCC who subsequently underwent initial IPTA were reviewed. Dynamic‐enhanced MRI were performed before IPTA and the criteria of HCC diagnosed was defined according to the American Association for the Study of Liver Diseases (AASLD). Figure 2.2The follow‐up duration was terminated in October 2022. The serum alpha‐fetoprotein (AFP) and dynamic contrast‐enhanced images were examined again at 1 and 3 months after IPTA and at approximately 3‐ to 6‐month intervals. Local tumor progression (LTP) was defined according to imaging results of abnormal nodular, disseminated, and/or unusual patterns of peripheral enhancement around the ablative site in patients treated with IPTA.2.32), and T1WI + C data. ROIs of HCC nodule were manually drawn along the tumor margin on T2WI  and T1WI + C  containing the tumors' chords and burrs, and ROIs were also placed on the high‐signal intensity region on DWI. Extended 5‐mm tumor margin of tumor was automatically reconstructed using erosion and dilation algorithm (MATLAB imerode and imdilate function). The 2D contour and 3D reconstruction of delineation is shown in Figure. The MRI raw data before and after IPTA were taken from the picture archiving and communication system (PACS) database. The multiparametric MRI data  of pre‐ablation and T1WI + C of post‐ablation were both collected. MRI scan parameters are described in Table 2.43 of isotropic spatial resolution. Radiomics features were extracted from above‐mentioned ROI using Pyradiomics package (https://www.radiomics.io/pyradiomics.html). ResNet18 pre‐trained on ImageNet and fine‐tuned on MRIs was used to extract DL features.U test. A random forest (RF) based feature selection method named Boruta to screen the most important features to differentiate LTP status.Multiparametric MRIs were normalized using Z‐score and nearest interpolation method to the standard normal distribution of image intensity and 1 × 1 × 1 mm2.5To develop and test the deep learning radiomics (DLR) based models, these patients were divided into two cohorts: one primary cohorts (PC) and two external test cohorts (ETCs). Multiparametric MRI features were further explored, and four different MRI signatures including T1WI + C, T2WI, DWI extracted from tumor, and T1WI + C extracted from ablative zone. The generated multichannel feature maps flattened into a one‐dimensional vector were treated as the resulted DLR‐based features Appendix . After a2.6Continuous variables were given as mean ± standard deviation (SD) or median with interquartile range (IQR) and compared by the Kruskal–Wallis test. Categorical variables were presented as frequencies with percentages and compared by the chi‐squared test. Univariate and multivariate logistic regression analyses were applied to calculate the hazard ratios (HRs) and corresponding 95% confidence interval (CI). The discrimination, and predictive performance of these models were assessed by areas under receiver operating characteristic curve (AUC) and compared by using DeLong test. The predictive accuracy, sensitivity (SENS), specificity (SPEC), positive predictive value (PPV), and negative predictive value (NPV) were also used to assess the performance of the prediction models. Survival curves were calculated using the Kaplan–Meier method and compared with the log‐rank test.p‐value of less than 0.05 was considered as statistical significance.A two‐tailed 33.1p < 0.05).We trained a DLR model to predict LTP based on pre‐ and post‐ablation multiparametric MRI in PC and performed validation on two independent ETCs. The 417 HCC patients  with 512 lesions  were screened in this study. Among them, 195 patients received radiofrequency ablation (RFA) and 222 patients received microwave ablation (MWA), respectively. The baseline characteristics of the patients between PC and two ETCs are outlined in Table 3.2p < 0.10) indicators of LTP in the univariable regression analysis were input in the multivariable regression model by backward stepwise elimination. Multivariate regression analysis found No. of tumor , AM , and location abutting major vessels  were significantly associated with LTP in the PC  + 4.125 × AM  +4.982 × No. of tumor  + 7.850 × DLR score.As a result, SVM method can achieve the highest AUC value  for classifying LTP on all MR sequences than that in other ML classifiers Table . Thus, t3.4The AUC, ACC, accuracy, SENS, SPEC, PPV, and NPV of all predictive models were shown in Table 3.5p < 0.001). The cumulative 1‐, 3‐, and 5‐ years OS rates were 100%, 84.5%, and 69.4%, in low‐risk group, which were significantly higher than 97.6%, 59.6%, and 8.0% in high‐risk group in ETC1 (p < 0.001). The cumulative 1‐, 3‐, 5‐ years OS rates were 100%, 87.5%, and 49.4%, in low‐risk group, which were significantly higher than 100%, 55.4%, and 12.4% in high‐risk group in ETC 2 (p = 0.002).The AUC of DLR‐clinical model in PC, ETC1 and ETC2 were compared and shown in Figure 4Over the last decade, with the development of ablation systems with water cooling cycles and utilizing artificial ascites, larger ablation zone and less heat‐sink effect for these IPTA technique can be found commonly, furthermore, the satisfactory treatment results and overall survival are easier to obtain.The finding of this study mainly included the following four aspects: (i) to the best of our knowledge, this is the first study that the ablation‐related multiparametric MRI data of a consecutive patients with early HCC were collected simultaneously at multiple high‐volume institutions, and used to develop and validate the DLR models based on for predicting LTP after IPTA; (ii) the predictive performance of DLR model based on multiparametric MRI combining feature between tumor and ablation area that select the more image information by supervised DL according to their reproducibility, which outperformed significantly clinical model; (iii) the integrative model comprising the DLR signatures and clinical variables were built and externally validated, that yields the optimal predictive performance among all models; (iv) this study provides evidence for predicting LTP in patients with HCC underwent IPTA, and it is potentially an important major step toward the availability of robust integrative model for the risk assessment and management in HCC patients.p < 0.001). Then, the integrative model comprising DLR signatures and clinical variables including number of tumor, safe margin, and location abutting major vessels improved the performance of DLR model, with AUC of 0.871 in PC, 0.869 in ETC1, and 0.869 in ETC2.In this study, four different classification methods including SVM, GBDT, LDA, and LR were tested, respectively. SVM showed superior performance among them and we adopt it for the following experiments. Previous studies indicated the radiomic features are enable to quantify tumor heterogeneity by extracting subtle imaging intensity variations, voxel arrangements, and using transformation such as wavelet to represent features at multiple scales.Previous reports have been conducted to analyze the risk factors and patterns of recurrence after IPTA.To improve the multidisciplinary treatment of HCC and reduce LTP rate, the HCC patients at high risk of therapeutic strategies including preventive and adjuvant therapy .There are certain limitations to our study. First, the sample size of this study was relatively small, the DLR integrative model may be mildly overfitted. Therefore, we must continue to collect MRI data to further confirm the predictive ability and robustness of the DLR based integrative model; Second, the parameters of MRI machine, IPTA technology selection (MWA or RFA) were different from multiple hospitals, these factors may influence the predictive performance of these DLR models; Third, we did not collect other potential molecular biomarkers, including NLR, MMP7, MUC1, and genomic information. The accuracy and robustness of the DLR‐based integrative model may be improved if combined with the above‐mentioned factors.In conclusion, the easy‐to‐use integrative model consisting of MRI signatures and clinical variables exhibited adequate performance, which was capable of individualized predictive ability that could stratify HCC patients underwent IPTA into different LTP risk groups. Therefore, this DLR‐based tool may help physicians in decision making after IPTA for early HCC in clinical practice and trials. In addition, external tests and designing prospective clinical trials should be performed to obtain more solid and reliable evidence in subsequent studies.Chao Chen: Writing – original draft . Qiuying Han: Writing – original draft . He Ren: Data curation . Siyi Wu: Formal analysis . Yangyang Li: Data curation . Jiandong Guo: Validation . Xinghai Li: Investigation . Xiang Liu: Supervision . Chengzhi Li: Writing – review and editing . Yunfei Tian: Writing – review and editing .None.The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.Appendix S1Click here for additional data file.


The rapid white matter (WM) maturation of first years of life is followed by slower yet long‐lasting development, accompanied by learning of more elaborate skills. By the age of 5 years, behavioural and cognitive differences between females and males, and functions associated with brain lateralization such as language skills are appearing. Diffusion tensor imaging (DTI) can be used to quantify fractional anisotropy (FA) within the WM and increasing values correspond to advancing brain development. To investigate the normal features of WM development during early childhood, we gathered a DTI data set of 166 healthy infants  and 144 healthy children . The sex differences, lateralization patterns and age‐dependent changes were examined using tract‐based spatial statistics (TBSS). In 5‐year‐olds, females showed higher FA in wide‐spread regions in the posterior and the temporal WM and more so in the right hemisphere, while sex differences were not detected in infants. Gestational age showed stronger association with FA values compared to age after birth in infants. Additionally, child age at scan associated positively with FA around the age of 5 years in the body of corpus callosum, the connections of which are important especially for sensory and motor functions. Lastly, asymmetry of WM microstructure was detected already in infants, yet significant changes in lateralization pattern seem to occur during early childhood, and in 5‐year‐olds the pattern already resembles adult‐like WM asymmetry. Significant and widely distributed differences between white matter microstructure of females and males were observed in 5‐year‐old healthy children with tract‐based spatial statistical analysis. Contrarily, no sex differences were observed in infants aged 2–5 weeks. Furthermore, the white matter microstructure showed significant left‐right lateralisation in both age groups, and the asymmetry pattern of 5‐year‐olds resembled the ones previously observed in adult populations. The exclusion criteria, in addition to general MRI contraindications, were the following: (1) Birth before gwk 35 (before gwk 32 for separate nested cohort with exposure to synthetic glucocorticoids during pregnancy), (2) major developmental disorder, (3) other types of long‐term diagnosis that requires constant contact to hospital, (4) sensory abnormalities (e.g. blindness or deafness), (5) use of daily, regular medication , (6) head trauma requiring inpatient care (reported by parents). The informed consent was collected from both parents.2.2b value 1000 s/mm, 96 noncollinear diffusion gradient directions divided into three scanning sets  with 9 b0 images . The scan visits included also structural and functional MRI scans  for infants and with a Siemens Magnetom Skyra fit 3T scanner (20‐element head/neck matrix coil) for 5‐year‐olds. The scanner was upgraded in between the two data collections. The Generalized Autocalibrating Partially Parallel Acquisition (GRAPPA) technique was used to accelerate imaging. Diffusion weighted imaging protocol was applied with a standard twice‐refocused Spin Echo‐Echo Planar Imaging (SE‐EPI): TR (time of repetition)/TE (time of echo) = 8500/90.0 ms (for infants) and 9300/87.0 ms (for 5‐year‐olds), FOV (field of view) = 208 mm, isotropic voxels with 2.0 × 2.0 × 2.0 mm resolution, The infants were imaged during natural sleep after being fed by (breast) milk. A vacuum mattress was used to reduce movement during the imaging. Soft mouldable silicone ear plugs and hearing muffs were used for hearing protection. Infant MR images included 12 subjects with incidental findings , which were handled according to the procedure described in our earlier work . b0 images, including at least one image per imaging set, were co‐registered and averaged , and the brain mask was created with Brain Extraction Tool (BET version 1.0.0) Smith,  with setp < .05 regarded as statistically significant). As the age and sex showed statistically significant correlations with FA, further analyses were performed with age and sex as main variables and other variables as covariates.General linear model (GLM) with FSL's randomise tool was used for voxel‐wise analysis of inter‐subject variation. In the infant group, sex, age from birth and gestational age, rotational and translational mean framewise displacement measures (to control intrascanner head motion), maternal pre‐pregnancy body mass index (BMI), birth weight, maternal smoking during pregnancy, and maternal socio‐economic status  low [elementary school] and medium [high school or occupational education], (2) high [examination from university or university for applied sciences]) were explored as independent contributors. For 5‐year‐olds, sex, age at scan, handedness, rotational and translational mean framewise displacement measures, maternal pre‐pregnancy BMI, ponderal index, maternal smoking during pregnancy and maternal SES were explored as independent contributors. The analyses were conducted with 5000 permutations and multiple comparison correction with threshold‐free cluster enhancement , maternal pre‐pregnancy BMI, maternal age at birth, maternal SES, smoking during pregnancy, prenatal exposure to corticosteroids or selective serotonin/serotonin‐noradrenaline reuptake inhibitors (SSRI/SNRI) during pregnancy, and maternal perinatal depressive/anxiety symptoms  to detect areas with significant variation. The mean image and standard deviation (SD) of lateralized values was calculated with fslmaths. Tract‐wise mean FA values were extracted with coregistration of JHU Neonate atlas , and asymmetric differences with one‐sample t test, with Bonferroni corrected p value thresholded at 0.001 (0.05/36 tracts). Effect sizes for group differences were estimated with Cohen's d. Comparison between asymmetries in a subcohort of 22 infants and 5‐year‐olds was conducted with paired t test with Bonferroni corrected p value threshold at 0.002 (0.05/22).Statistical analyses for tract‐wise extracted mean FA values were performed with SPSS version 27.0 . Tract‐wise sex differences were estimated with independent samples 33.13.1.1Sex showed no statistically significant correlation with FA values in the infants after controlling for age at scan and gestational age, intrascanner head motion, birth weight, maternal BMI, SES, and smoking.3.1.2A significant effect of sex on FA values was detected in widespread regions at the age of 5 years, and was statistically strongest in posterior and temporal parts, and in the right hemisphere Figure . Females3.23.2.1p < .01) with FA values after controlling for age from birth and sex  after controlling for the gestational age and sex. The effect of gestational age on FA values was greater compared to the effects detected after birth. The results remain significant after controlling for intrascanner head motion, prenatal exposure to smoking, maternal age, pre‐pregnancy BMI and SES. The covariates included in the sensitivity analyses did not affect the results. We inspected the age effects also separately in females and males and observed no difference in association between gestational age and FA after controlling for age after birth or other covariates between males and females. When inspected separately, the age after birth and FA showed positive association in males (p < .05 after controlling for covariates), but the result did not remain statistically significant in females.The gestational age showed wide statistically significant positive correlations p < .0 with FA 3.2.2p < .06, with which also an additional cluster in left frontal area was observed; See Figure Sp = .08).Within our age range of 5.1–5.8 years, the age was positively correlated with FA values in the body of corpus callosum (BCC) Figure . After c3.33.3.1p < .01; results with p < .05 in Figure SLateralization of brain WM was detected in infants in multiple tracts. Leftward lateralized WM regions are depicted in Figure 3.3.2p < .001 in Figure p < .05 in Figure SThe WM structure was highly lateralized at the age of 5 years  and 5‐year‐olds (N = 144). In the group of 22 that were included in both the infant cohort and the 5‐year‐olds, the difference between lateralized FA in infants and 5‐year‐olds were statistically significant (p < .002) for CST, PLIC, anterior corona radiata and CG. Mean FA values of each tract in infants and in 5‐year‐olds are provided in Table SDifferences in left–right lateralization of WM tracts between infants and 5‐year‐olds was compared in subset of 22 subjects included in both age groups Figure . The det4We found widespread sex differences in white matter FA values in our sample of healthy, typically developing ca. 5‐year‐olds. Females had higher FA in all areas with significant differences, which were widely scattered throughout WM tracts. Sex differences were not detected in infants. Additionally, significant hemispheric asymmetries of FA values were observed in multiple WM tracts both in infants and at the age of 5 years. Hemispheric lateralization pattern was detected not to stay stable from birth to the age of 5 years. Lastly, age was positively associated with FA values during 6th year of life in mid‐posterior part of the corpus callosum.Sex differences in WM tract structure were expected based on prior studies Table . The preHemispheric asymmetries of WM microstructure appear early  and is addressed for future longitudinal studies with more optimal data for observing developmental changes. Also, significant positive correlation between the age and FA of BCC was detected even in a narrow age range between 5.1 and 5.8 years. The posterior BCC and the isthmus of CC contain the primary somatosensory and motor fibres , data pre‐processing, formal analyses, writing the manuscript draft. Harri Merisaari: designing data processing pipeline, writing the manuscript. Elmo P. Pulli, Anni Copeland, Eero Silver: data collection (5‐year‐olds), writing the manuscript. John D. Lewis and Jani Saunavaara: designing the MR acquisition protocol, writing the manuscript. Satu J. Shulist: data collection (infants), writing the manuscript. Riitta Parkkola: radiological evaluation of the MR images, writing the manuscript. Tuire Lähdesmäki: neurological evaluation of the infants, writing the manuscript. Linnea Karlsson and Hasse Karlsson: establishing the cohort, building infrastructure for carrying out the study, writing the manuscript. Jetro J. Tuulari: study conception, funding acquisition, supervision of Venla Kumpulainen, building the pre‐processing pipelines.The study was approved by the Ethics Committee of the Hospital District of Southwest Finland , and performed in accordance with the Declaration of Helsinki.Both parents of the participating child signed a written informed consent form. The child assent was assured prior to neuroimaging visits.None.Data S1. Supporting InformationClick here for additional data file.


Post‐stroke inflammation increases the risk of functional disability through enlarged cerebral infarct size directly and follow‐up stroke event indirectly. We aimed to use post‐stroke proinflammatory cytokine interleukin‐6 (IL‐6) as a marker of inflammatory burden and quantify post‐stroke inflammation's direct and indirect effect on functional disability.We analyzed patients with acute ischemic stroke admitted to 169 hospitals in the Third China National Stroke Registry. Blood samples were collected within 24 h of admission. Stroke recurrence and functional outcome measured by the modified Rankin scale (mRS) were assessed via face‐to‐face interviews at 3 months. Functional disability was defined as an mRS score ≥2. Mediation analyses under the counterfactual framework were performed to examine the potential causal chain in which stroke recurrence may mediate the relationship between IL‐6 and functional outcome.Among the 7053 analyzed patients, the median (interquartile range [IQR]) NIHSS score was 3 (1–5), and the median (IQR) level of IL‐6 was 2.61 (1.60–4.73) pg/mL. Stroke recurrence was observed in 458 (6.5%) patients, and functional disability was seen in 1708 (24.2%) patients at the 90‐day follow‐up. Per stand deviation (4.26 pg/mL) increase in the concentration of IL‐6 was associated with an increased risk of stroke recurrence  and disability  within 90 days. Mediation analyses revealed that 18.72%  of the relationship between IL‐6 and functional disability was mediated by stroke recurrence.Stroke recurrence mediates less than 20% of the association between IL‐6 and functional outcome at 90 days among patients with acute ischemic stroke. In addition to typical secondary prevention strategies for preventing stroke recurrence, more attention should be paid to novel anti‐inflammatory therapy to improve functional outcomes directly. Stroke recurrence mediates less than 20% of the association between post‐stroke proinflammatory cytokine interleukin‐6 and functional outcome at 90 days among patients with acute ischemic stroke. Written informed consent was obtained from each participant or his/her representative before data collection. This report follows A Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies reporting guideline.2.1We extracted data from the Third China National Stroke Registry (CNSR‐III), a large‐scale nationwide prospective registry of acute ischemic cerebrovascular events in China. Details for study design and patient identification of the CNSR‐III were reported elsewhere.For the current analysis, we included patients from 169 sites participating in the prespecified biomarker substudy and the imaging substudy. We excluded TIA patients and ischemic stroke patients with prior functional disabilities, patients who received reperfusion therapy (intravenous thrombolysis or thrombectomy), and patients with missing data on IL‐6 or 3‐month mRS scores.2.2Baseline data were collected by trained research coordinators following a standard data collection protocol that the steering committee developed. Baseline data include demographics ; National Institutes of Health Stroke Scale  score; pre‐stroke modified Rankin Scale  score; systolic blood pressure (SBP); diastolic blood pressure (DBP); smoking status; and medical history, including prior stroke or TIA, hypertension, diabetes, dyslipidemia, coronary heart disease or myocardial infarction(CHD/MI), and atrial fibrillation.Blood samples within 24 h of admission were collected. Plasma specimens were extracted, aliquoted, and transported through the cold chain to the central laboratory in Beijing Tiantan Hospital and stored at −80°C until tests were performed centrally and blindly. The concentration of IL‐6 was measured without technical repeat by using enzyme‐linked immunosorbent assay kits .Imaging data were collected in Digital Imaging and Communications in Medicine (DICOM) format on discs and sent to the imaging research center of Beijing Tiantan Hospital. Acute infarction was diagnosed according to hyperintensity on diffusion‐weighted imaging and was further classified as single acute infarction (uninterrupted lesions visible in contiguous territories), multiple acute infarctions , or watershed infarction.2.3Trained research coordinators followed patients in face‐to‐face interviews based on a standardized interview protocol 90 days after symptom onset. The stroke recurrence was defined as a new neurological deficit lasting more than 24 h or rehospitalization with a diagnosis of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The functional disability was defined as an mRS (range of 0[no disability] –6 [death]) score ≥ 2, as approximately half of the ischemic strokes were minor strokes in the CNSR‐III registry.2.4The study population was categorized according to quantiles of IL‐6 level. Normality for continuous variables was tested by Shapiro–Wilk tests and checked by Q‐Q plots as well. Baseline characteristics were described using means and standard deviations or medians and interquartiles for continuous variables and frequencies and percentages for categorical variables. Comparisons between groups were conducted using analysis of variance (ANOVA) or Kruskal–Wallis tests for continuous variables and chi‐square tests for categorical variables. We used a SAS macro called %ggBaseline to produce the baseline table automatically.We used a directed acyclic graph to illustrate the association of IL‐6 with functional disability and follow‐up stroke recurrence Figure . We perfAll hypothesis tests were 2‐tailed with a type‐1 error rate fixed at 5%. All statistical analyses were performed using SAS V.9.4 software (SAS Institute Inc.).2.5We performed a series of sensitivity analyses to test the robustness of our analysis. First, to avoid the competing risk with death, we re‐performed the mediation analysis after excluding patients who died before stroke recurrence. In addition, to check whether the mediation effect was affected by admission time, stroke severity, infarction pattern, infarction location, and subtype of ischemic stroke, we performed causal mediation analysis stratified by onset‐to‐door time , NIHSS score , infarction pattern, infarction location, and TOAST classification. Furthermore, we re‐assessed the association of IL‐6 with stroke recurrence and disability and re‐estimated the mediated effect of stroke recurrence on different scales of IL‐6 concentration, including original‐scale, log‐scale, and per standard deviation (SD) of log‐scale. Considering the impact of infarction volume, we provided a set of supplemental mediation analyses with the adjustment of infarction volume in the models as well.3We obtained data from 11,384 patients with acute ischemic stroke without baseline disability and without reperfusion treatment, excluding 3782 patients with TIA, mRS ≥ 2, or receiving reperfusion treatment from 15,166 admissions. After further exclusion of 4331 patients without blood or imaging samples, who had missing data on IL‐6 or lost to follow‐up, we finally included 7053 patients in the current analysis Figure . Baselinn = 2193) of patients were women, and the median (IQR) NIHSS score was 3 (1‐5). Hypertension (62.8% [n = 4430]) was the most common disease history, followed by diabetes (24.5% [n = 1731]) and prior stroke/TIA (22.5% [n = 1584]). Nearly one‐half of the patients had a single infarction (47.0% [n = 3317]) and 56.9% [n = 4016] of patients had infarcts in the anterior circulation. For etiology classification, one‐quarter of patients were LAA (25.7% [n = 1810]), and another quarter was SAO (25.7% [n = 1813]) , had a severer stroke at admission (median[IQR] of NIHSS score: 4.0 (2.0–7.0) vs. 3.0 [1.0–5.0]; p < 0.001), and more vascular risk factors, including prior stroke/TIA , hypertension , diabetes , dyslipidemia , CHD/MI , and atrial fibrillation . In addition, more multiple infarctions , simultaneous anterior and posterior circulatory infarctions , and the LAA subtype of ischemic stroke  were seen in the highest quartiles of IL‐6 (Table The median (IQR) IL‐6 concentration was 2.61 (1.60–4.73) pg/mL. Figure 3.2During the 90‐day follow‐up, stroke recurrence and functional disability were seen in 458 (6.5%) and 1708 24.2%) patients, respectively. After adjusting for covariates, patients with the highest quartile of IL‐6 levels had a non‐significantly 27% higher risk of stroke recurrence  and a significantly 59% higher risk of disability  at 90 days. We also treated IL‐6 concentration as a continuous variable. We found that per SD (4.26 pg/mL) increase in IL‐6 concentration was associated with a significantly 19% increased risk of stroke recurrence  and a significantly 22% increased risk of disability  at 90 days (Table 4.2% pati3.3n = 277) and 83.8% (n = 1431) of the 1708 functionally disabled patients, respectively. Table Stroke recurrence before disability and disability without stroke recurrence was seen in 16.2%  of 11,384 patients were excluded from this analysis because of no biomarker or imaging samples or missing data on IL‐6 or 90‐day follow‐up mRS, which may introduce selection bias. However, 95% (n = 4110) of the 4331 patients were excluded because they enrolled from a site not participating in the biomarker and imaging substudy. In addition, baseline characteristics between included and excluded patients were largely comparable. Therefore, we believe that the selection bias would be minimized in this study. Second, patients were recruited up to 7 days after stroke onset, which may introduce heterogeneity because of the admission time. However, over 50% of the blood sample were collected within 55 h after symptom onset, which would reduce the heterogeneity. In addition, subgroup analysis by admission time showed similar mediation effects. Third, during hospitalization, infections may affect the level of IL‐6 and the estimation of the mediation effect. However, the rate of pulmonary infection was only 4.9% (n = 343), and urinary system infection was only 1.3% (n = 91) among the included patients. In addition, we could not precisely judge whether these infections occurred before or after blood samples were taken. Fourth, the concentration of IL‐6 had a skewed distribution, which may affect the estimations of the mediation effect. However, sensitivity analyses on different scales of IL‐6 revealed stable and reliable results. Fifth, although potential covariates were carefully selected and adjusted for in the models when assessing the mediating effect, other unmeasured confounders may still exist. Finally, we exclude patients with prior functional disability and patients who received reperfusion therapy. Therefore, our conclusions may not be generalized to these populations.This study has several limitations. First, 38.0% , Beijing Natural Science Foundation (Z200016), the National Natural Science Foundation of China , and the Beijing Municipal Science & Technology Commission (Z181100001818001).None.Appendix S1Click here for additional data file.


Interstitial lung disease (ILD) can manifest before the diagnosis of primary Sjögren's syndrome (pSS), however, the underlying mechanisms remain unclear. The aim of this study is to investigate the characteristics of lung‐onset pSS using chest high‐resolution computerized tomography (HRCT) and pulmonary function tests (PFTs).The data of 102 patients with pSS‐ILD were retrospectively analyzed. The patients were divided into two groups: lung‐onset group and the nonlung‐onset group. The chest HRCT, PFTs, and clinical and laboratory data were evaluated and compared.p = .014). Total lung capacity (TLC) (%pred)  and forced vital capacity (FVC) (%pred)  were significantly lower in the lung‐onset group, compared with the nonlung‐onset group. Residual volume (RV)/TLC (%) significantly increased more than 40% in the lung‐onset group (p = .015). Restricted ventilation disorder, small airway obstruction and reduced diffusing capacity of the lung for carbon monoxide/alveolar volume (%Pred) were more common in the lung‐onset group . Correlation analysis showed that HRCT score was positively correlated with the interval between the onset of pulmonary symptoms and the diagnosis of ILD, serum CA125, and serum CEA. TCL (%pred), VC (%pred), FVC (%pred) were negatively correlated with serum CA125.Among the 102 patients with pSS‐ILD, 59 (57.8%) were lung‐onset and 43 (42.2%) were nonlung‐onset. Chest HRCT in the lung‐onset group showed higher percentage of usual interstitial pneumonia and nonspecific interstitial pneumonia, the difference did not reach statistical significance. The total HRCT score was higher in the lung‐onset group, compared with the nonlung‐onset group (2 , vs. 2 , Lung‐onset is common in pSS patients with more severe lung function impairments. Serum biomarkers, such CA125, CEA, and ALB, were associated with the severity of lung damage. Lung‐onset is common in primary Sjögren's syndrome patients, and these patients present with more severe lung function impairments. Serum biomarkers, such CA125, CEA, and ALB were associated with the degree of lung damage. As a systemic autoimmune exocrine disease, pSS affects multiple organs, including blood, gastrointestinal system, kidney, skin, lungs, and nervous system.High‐resolution computed tomography (HRCT) scans have shown lung changes in 34%–50% of pSS patients.Our previous studies indicate that the proportion of nonsicca‐onset is higher in the pSS‐ILD patients. Functional impairments of the lungs are associated with poor survival rate.22.1This was an observational and retrospective study. A total of 527 pSS patients were screened at Beijing Chaoyang Hospital between 2011 and 2020. One hundred and two patients with pSS‐ILD were included , history of disease, smoking history, clinical symptoms , physical signs, and laboratory examinations.Laboratory examinations include the following: the levels of immunoglobulins , serum complement C (C3 and C4), C‐reactive protein (CRP), Rheumatoid factor (RF) and erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), albumin (ALB), tumor markers , as well as the presence of antinuclear antibodies (ANA), anti‐Ro/SSA and anti‐La/SSB.2.3The classification of chest HRCT was conducted by two experienced radiologists. HRCT patterns were categorized according to the 2013 international multidisciplinary classification of idiopathic interstitial pneumonia (IIP),The HRCT findings in each case of interstitial lung abnormalities (ILA) was scored by a four‐point scale . The predominant distribution of lesions was classified as being predominantly peripheral, peribronchovascular, or mixed.The following PFTs data were obtained from patient charts: total lung capacity (TLC), vital capacity (VC), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), residual volume (RV), forced expiratory flow (FEF25/50/75) and diffusing capacity of the lung for carbon monoxide/alveolar volume (DLCO/VA). PFTs were shown as percentages of the predicted value of each parameter for each individual based on the age, gender and height. The damages to lung function mainly include obstructive ventilation disorder (OVD)., restricted ventilation disorder (RVD) , small airway obstruction (SAO) , reduced diffusion capacity (RDC) [DLCO/VA (%Pred) <80%] and mixed ventilatory dysfunction (MVD) (OVD and RVD).2.4t test or Mann–Whitney U test were used for two group comparisons. One‐way analysis of variance and LSD were used for multiple comparisons. Frequencies were analyzed using χ2 test or Fisher's exact test. Pearson correlation coefficient was used for the correlation between two continuous variables. Results were considered statistically significant if p < .05.SPSS 22.0 software was used for statistical analysis. Quantitative data was expressed as Mean ± standard deviation (SD). Continuous variables were expressed as either mean ± SD or Median and range. Independent samples 33.1Among the 102 pSS patients with ILD, 91 (89.2%) were female, 11 (10.8%) were male. The mean age of ILD‐onset, pulmonary symptoms‐onset and nonlung symptoms‐onset were (62 ± 10) years, (61 ± 10) years, and (58 ± 11) years, respectively. The median respiratory duration and non‐respiratory symptoms duration were 12  months and 36  months, respectively. Only 15 (14.7%) patients were smokers, and the duration of smoking was 20  years  or ILD . The most common manifestation at onset was sicca symptoms , joint involvement , Raynaud's phenomenon , saprodontia , parotid gland swelling , and minor salivary gland biopsy positive .The manifestation of lung‐onset patients were pulmonary symptoms  from pSS‐related manifestations to pSS‐ILD diagnosis was 24  months. Only 4 (3.9%) patients had ILD diagnosis before pSS with the median diagnosis time of 41  months. The median diagnosis time from pulmonary‐onset to pSS‐ILD was 6  months. Although the presence of sicca symptoms was the most common manifestation, 26 (25.5%) patients were diagnosed with pSS based on lung manifestation.Autoantibody analyses revealed that anti‐Ro/SSA and anti‐La/SSB were positive in 74.5% (76/102) and 19.6% (20/102) of pSS‐ILD patients. A total of 28 (27.5%) patients underwent a labial salivary gland (LSG) biopsy. Percentages of patients with ANA and RF were 85.3% (87/102) and 29.4% (30/102), respectively.3.2HRCT patterns of 102 patients were analyzed. The most frequent HRCT finding was the multiple HRCT patterns 34.3%) coexisted with OP, NSIP, and UIP, followed by the single HRCT pattern (51%), such as UIP, NSIP, Unclassified pattern, OP, and LIP (Table 4.3% coexPFTs findings indicate that TLC (%Pred) (78.61 ± 18.69) was less than 80%, VC (%Pred) 85.45 ± 23.07) and FVC (%Pred) (86.21 ± 24.19) were more than 80%; FEV1 (%Pred) (82.34 ± 21.97), FEV1/FVC (%) (80.50 ± 8.29) were more than 80%; and RV/TLC (%) (41.66 ± 8.14) was more than 35%, MEF25 (%Pred) (61.48 ± 29.38) and MEF50 (%Pred) (67.34 ± 27.37) were less than 70%, MEF75 (%Pred) (83.69 ± 35.11) was more than 80%; DLCO/VA (%Pred) (68.08 ± 24.95) was less than 70% . The interval between pSS‐related manifestation and ILD diagnosis was significantly longer in the non‐lung‐onset group (p = .000). The interval between pulmonary symptoms onset and ILD was significantly longer in the lung‐onset group (p = .000). In the lung‐onset group, 40 cases initiated with ILD, and four cases had ILD before pSS.The clinical characteristics are shown in Table p = .454). Sicca symptoms  were more common in the nonlung‐onset group . Pulmonary symptoms  were more predominant in the lung‐onset group .Ten (16.9%) patients were smokers in the lung‐onset group, and 5 (11.6%) patients were smokers in the nonlung‐onset group , whereas IgM, C3 and C4 were similar. Serum LDH level was higher in the lung‐onset group (p = .018). The serum level of CEA and CA125 were similar between two groups . In lung‐onset group, the percentage of UIP and NSIP were higher, but the difference did not reach statistical significance  was most common, especially with NSIP feature .In addition, 59 patients in the lung‐onset group and 43 patients in the nonlung‐onset group underwent HRCT. The total HRCT score was higher in the lung‐onset group   Table . Three pp = .049 and p = .050, respectively). Compared with the nonlung‐onset group, RV/TLC (%) significantly increased more than 40% in the lung‐onset group (p = .015). MEF25 (%Pred), MEF50 (%Pred) and MEF75 (%Pred) were normal. DLCO/VA (%Pred) in both groups were less than 80% , whereas the percentages of OVD and MVD were similar . RDC was predominant in both lung‐onset and nonlung‐onset groups (56[96.6%] vs. 37[86%]).RVD and SAO were more common in the lung‐onset group , but was not correlated with the interval between the onset of pSS‐related manifestation and ILD diagnosis.Correlation analysis showed that HRCT score was positively correlated with the interval between pulmonary symptoms onset and the diagnosis of ILD (months)  and CEA . However, HRCT score was negatively correlated with serum ALB concentration . There was no correlation with other immune indexes. HRCT score was negatively correlated with TCL (%pred) , VC (%pred) , FVC (%pred) , FEV1 (%pred)  and DLCO/VA (%Pred) . TCL (%pred) was negatively correlated with serum LDH concentration . DLCO/VA (%Pred) was postively correlated with serum ALB concentration . TCL (%pred) , VC (%pred)  and FVC (%pred)  were negatively correlated with serum level of CA125.HRCT score was positively correlated with serum level of CA125  the pulmonary symptoms‐onset age and ILD‐onset age were younger. (2) Chest HRCT features were more severe. (3) The small airway and alveolar impairment were severe. (4) Autoantibodies positive rate was lower. (5) HRCT score was positively correlated with elevated serum CA125 and CEA. (6) PFTs indexes  were negatively correlated with the elevated serum CA125.p = .006 and p = .009, respectively) in the lung‐onset group. However, Gao et al. showed that the age between sicca‐onset and nonsicca‐onset group was similar.The mean age of ILD‐onset [(61 ± 10) years] was similar to previous reports.In the present study, although sicca symptoms were the most common manifestation at the onset of pSS , more than half of the pSS‐ILD patients had pulmonary symptoms as the first manifestation, including dry cough (88.1%) and panting after activity (81.4%). In pSS patients, the most common symptom of airway diseases was cough with an incidence of 41%–61%. The severity of cough was correlated with the degree of airway inflammatory and poor quality of life.In clinical practice, subclinical lung disease and ILD are common. In the lung‐onset group, 32.4% of patients started with pulmonary symptoms, 25.5% of patients were diagnosed with pSS due to ILD. Four cases had ILD before pSS. A Spanish multicenter study has reported 25 pSS patients with ILD. Among them, 60% had ILD before pSS.p = .027, r = .238). Therefore, patients should be screened for ILD after the onset of respiratory symptoms.In the nonlung‐onset group, the median interval between the pSS‐related manifestation and ILD diagnosis was longer, whereas the median interval between pulmonary onset and ILD was shorter (2 months). Previous studies have indicated that pulmonary involvement presents in pSS patients with longer disease duration.For pSS, ILD is traditionally associated with smoking, aging, hypergammaglobulinemia, increased RF or ANA titers, anti‐Ro/SSA or anti‐La/SSB positivity, elevated CRP, and reduced serum C3 levels.Interestingly, in our study, the positive rate of antibodies and the serum IgG/IgA were lower in the lung‐onset group. Similarly, Gao et al. demonstrated a low anti‐Ro/SSA and anti‐La/SSB rate in the nonsicca group.B and T cells play important roles in the pathogenesis of pSS. Previous studies have shown that the frequency of abnormal ocular and oral diagnostic tests were higher in anti‐La/SSB positive patients.On the contrary, many bronchoalveolar lavage fluid (BALF) studies have indicated CD4+T lymphocytic alveolitis in pSS patients without respiratory symptoms.The most common HRCT type of ILD in pSS is NSIP (41%–45%), followed by UIP (10%), OP (4%) and LIP (4%–8%). Our study indicated that the most frequent HRCT finding was the multiple HRCT patterns coexisted with OP, NSIP and UIP, followed by UIP, NSIP, unclassified pattern, OP and LIP. Our previous study has demonstrated that 40% of patients are classified as coexistence of multiple HRCT modes, among which the mixed mode of NSIP and OP (43.9%) and the mixed mode of NSIP and UIP (35.4%) are more common.Our study indicates that the NSIP feature is most common in the nonlung‐onset group. Gao et al. have demonstrated that NSIP pattern is the most common pattern in the sicca‐onset group, followed by UIP. There was no difference between nonsicca‐onset and sicca‐onset. Nevertheless, the proportion of LIP pattern was higher in the sicca‐group.p = .014), which is consistent with others studies.The imaging features of pSS‐ILD are complex and may overlap with other diseases. There are combinations of multiple variables, such as ground glass opacity, consolidation, reticular abnormality, honeycomb, cyst, and so on. First, different features may affect a variety of anatomical structures, such as the airways, alveoli, blood vessels, pleura, and so on. Second, the coexistence of multiple variables, such as the mixture of NSIP and OP, the mixture of NSIP and UIP, and the mixture of NSIP and LIP, suggests that nonuniformity and overlap of histopathological abnormalities can coexist in one patient. The diversity may attribute to different immunological mechanisms or different stages of immunological injury in the lung. The prognostic indicators related to variable abnormalities of pSS‐ILD will be investigated in our future studies. In the present study, the lung‐onset group had a higher total HRCT score , accompanied with lower TLC (%Pred), VC (%Pred) and FVC (%Pred) values . DLCO/VA (%Pred) and MEF25‐50 (%Pred) was less than 70% in the lung‐onset group. The PFT defects suggest that small airway and alveolar impairment are more prominent in the lung‐onset group. Correlation analysis shows that HRCT score was negatively correlated with TCL (%pred), VC (%pred), FVC (%pred), FEV1 (%pred), and DLCO/VA (%Pred).PFT in pSS can be restrictive and obstructive with low DLCO and small airway disease even in patients without pulmonary symptoms.Reduced DLCO, FVC impairment, and fibrosis are commonly seen in patients with ILD.Our results indicate that patients with severe lung impairments are more likely to be diagnosed with lung disease other than pSS. The delayed diagnosis of pSS is often due to the nonspecificity of the initial symptoms.p = .018), and was negatively correlated with TCL (%pred). In addition, hypoproteinemia was a risk factor for the progression of ILD and an independent risk factor for mortality in pSS‐ILD patients.Serum LDH is a traditional biomarker for ILD,In recent years, tumor markers have been found to be associated with ILD in CTD. In this study, the serum level of CA125 and CEA were high in the lung‐onset group. However, HRCT score was positively correlated with serum CA125 and CEA. Moreover, elevated CA125 level was correlated with decreased TCL (%pred), VC (%pred) and FVC (%pred). A retrospective analysis of 706 patients with pSS showed that the serum level of CEA and CA125 were significantly elevated in pSS‐ILD patients, and CEA was significantly related to the onset of pSS‐ILD.The present study has several limitations. First, this is a retrospective study. Second, this was a single center study, which may limit the generalization of the results. Third, we only focus on the HRCT and PFTs of the pSS‐ILD patients, and the data on treatment and prognosis were not included. In the future, we will explore treatment and prognosis.5In conclusion, the present study is the first one that investigated the features of chest HRCT and PFTs in the lung‐onset pSS patients. Lung‐onset is common in pSS patients, which poses a challenge for rheumatologists to establish the diagnosis because of the lack of sicca symptoms and the lower presence of antiautoantibodies. Some respiratory symptoms can be the initial manifestation of pSS. High HRCT score, reduced DLCO/VA and FVC impairment are more common in the lung‐onset group. Serum biomarkers, such CA125, CEA and ALB are associated with the degree of lung damage. Therefore, pSS‐ILD patients with lung‐onset should receive effective treatments for their pulmonary damages.Xin Dong: Data curation; formal analysis; methodology; supervision; writing—original draft; writing—review and editing. Yanli Gao: Conceptualization; data curation; methodology; supervision. Man Li: Data curation. Dong Wang: Data curation; methodology. Jifeng Li: Data curation; formal analysis. Yongfeng Zhang: Conceptualization; data curation; formal analysis; methodology; software; validation; writing—original draft; writing—review and editing.The authors declare no conflicts of interest.