Our aim was to assess associations between cardiorespiratory fitness (CRF) and body mass index (BMI) in youth and 5‐year mortality after site‐specific cancer diagnoses in men.2) was classified as underweight (<18.5), normal weight (18.5–24.9), overweight (25–29.9), or obesity (>30). Conscription data were linked with register data on cancer diagnosis and mortality. Analyses included CRF, BMI, date of diagnosis, and age, year, and center for conscription.Men with cancer from a population who underwent military conscription at ages 16–25 during 1968–2005 in Sweden were included. CRF was assessed as maximal aerobic workload on a cycle ergometer test and was classified as low, moderate, or high. BMI , malignant skin cancer (HR 0.80), non‐Hodgkin lymphoma (HR 0.78), and cancer in the lungs (HR 0.80), head and neck (HR 0.68), pancreas (HR 0.83), stomach (HR 0.78), liver (HR 0.84), rectum (HR 0.79), and bladder (HR 0.71). Overweight and/or obesity were associated with increased mortality after any cancer , malignant skin cancer (HR 2.03), Hodgkin lymphoma (HR 2.86) and cancer in the head and neck (HR 1.38), thyroid (HR 3.04), rectum (HR 1.53), kidney (HR 1.90), bladder (HR 2.10), and prostate (HR 2.44).We report dose‐dependent associations between CRF and BMI in youth and mortality after site‐specific cancer diagnoses in men. The associations with mortality could be due to both cancer inhibition and an improved tolerance to withstand cancer treatment. These results strengthen the incentive for public health efforts aimed at establishing a high CRF and normal weight in youth. Fitness and body mass index was assessed at age 18 in 1.2 million men. Analyses of associations between fitness and fatness in youth and 5‐year mortality after subsequent cancer diagnoses showed a lower mortality after several of the site‐specific cancers with higher fitness and normal body mass index. However, several of the previous studies mix pre‐ and postdiagnosis assessments, long‐ and short‐term mortality, as well as mortality in patients diagnosed with cancer and cancer‐specific mortality in the general population, and data are lacking for most site‐specific cancers. The potential for improving 5‐year mortality through establishing a healthy lifestyle is still inadequately explored for most cancer sites.22.1This is a Swedish nationwide, register‐based observational cohort study with prospective data. Ethical permission for the study was obtained November 16, 2021 from the Swedish authority for ethical permissions, EPN Dnr 462‐14 with addendums Dnr 2021‐05638‐02 and 2023‐04937‐02. No consent was obtained from participants since data were retrieved from registers.2.2All men who underwent the compulsory conscription exam from 1968 to 2005 at the age of 16–25 years, with valid information on CRF and BMI and who subsequently were diagnosed with any cancer were included. The World Health Organization defines “youth” as the 15‐ to 24‐year age group.2.3Participants were identified in the Swedish military service conscription register.2.42.4.1max), as described previously.Information on CRF at conscription was assessed as maximal aerobic workload in units of Watt from a cycle ergometer test (W2.4.22 and categorized into underweight (<18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obesity (≥30 kg/m2).Height and weight were measured, and BMI was calculated as kg/m2.52.5.1Information on cancer diagnoses was collected from the Swedish National Patient Register2.5.2Information on date of death was retrieved from the Swedish cause of death register.2.62.6.1Two test procedures were used for muscle strength, previously described in detail.2.6.2Parental level of education was used as socioeconomic status and was collected from Statistics Sweden and categorized according to highest level attained by any parent: up to 9 years of compulsory school, high school ≤2 years at university, or ≥3 years at university.2.6.3For most individuals in this study, there was no information on smoking status. In 1968–1970, questions on smoking were included in the conscription and categorized in our analyses: No active smoking, 1–10 cigarettes or equivalent per day, and > 10 cigarettes or equivalent per day.2.7A statistical analysis plan was specified before any statistical analyses were performed . No poweCox proportional hazards models were used to assess the associations between CRF and BMI in youth and the 5‐year mortality following site‐specific cancer diagnoses. Follow‐up started at date of cancer diagnosis until date of death and was censored at first emigration, end of follow‐up , and 5 years after diagnosis. The outcome was any mortality. The primary analyses for CRF assessed linear associations between the standardized CRF score (1–9), and supplementary analyses were explored with categorical comparisons (moderate and high vs. low CRF) to facilitate interpretation of the effect sizes. For BMI, the primary analysis was done for categorical comparisons  since a U‐shaped trend was anticipated with respect to mortality. The proportional hazards assumption was checked graphically, and no major deviations were observed. Results were given in terms of hazard ratios (HR) with 95% confidence intervals (CI). The statistical analysis plan detailed the covariates to be included in the models, according to a directed acyclic graph. The main analyses included date of cancer diagnosis, the following covariates assessed at the time of conscription: year, age, conscription center, and CRF and BMI. Missing data led to listwise deletion since rate of missing information was low for all included covariates. A sensitivity analysis was performed in a subpopulation with information on smoking to see how adjusting for smoking changed the estimates.After performing the first analysis, we identified the need to include date of cancer diagnosis to account for changes in cancer outcomes over time. Combined with year of conscription, this effectively also adjusts for age at diagnosis. The pre‐specified analysis was to be performed for all site‐specific cancers regardless of other previous cancers in the individual. After performing the pre‐specified analyses, we identified the need to add an analysis restricted to the first cancer diagnosis in each participant. Sensitivity analyses were also performed to see whether including parental education, age at diagnosis, or muscle strength as covariates in the models changed the results. Missing values lead to listwise deletion.3From the population of 1,237,611 men, 85,139 were diagnosed with a cancer, of whom 84,621 received their cancer diagnosis before possible date of death Table . Men wit3.1p < 0.001, hazard ratio [HR] for high vs. low CRF 0.70, 95% confidence interval [CI] 0.67–0.74, Table There was a linear association between the 9‐grade CRF scale in youth and 5‐year mortality after any cancer diagnosis  or BMI  and 5‐year mortality after CNS cancer diagnosis . However, obesity was associated with a threefold increased mortality when including all thyroid cancers , while there was no association between CRF and mortality after kidney ; data curation ; formal analysis (lead); funding acquisition ; investigation (lead); methodology (lead); project administration ; visualization ; writing – original draft (lead); writing – review and editing (lead). Kirsten Mehlig: Conceptualization ; data curation (lead); formal analysis (supporting); investigation ; methodology ; software ; validation (lead); visualization ; writing – original draft (supporting); writing – review and editing . Elin Ekblom‐Bak: Conceptualization (supporting); investigation ; methodology; writing – original draft (supporting); writing – review and editing . Lauren Lissner: Conceptualization (supporting); funding acquisition ; investigation ; methodology ; project administration (supporting); supervision (supporting); writing – original draft (supporting); writing – review and editing . Mats Börjesson: Conceptualization (supporting); funding acquisition ; investigation ; methodology ; supervision ; writing – original draft (supporting); writing – review and editing . Maria Åberg: Conceptualization ; data curation (supporting); formal analysis (supporting); funding acquisition ; investigation ; methodology ; project administration (supporting); resources ; supervision ; validation (supporting); writing – original draft (supporting); writing – review and editing .This work was supported by grants from the Swedish state under the agreement between the Swedish Government and the county councils, the ALF‐agreement , Assar Gabrielsson's foundation (FB21‐04), the Swedish Research Council (2022‐00166), and the Heart and Lung Foundation (20180379). The funders had no role in planning, interpreting, or reporting the results of the study.www.icmje.org/coi_disclosure.pdf and declare: EEB, MÅ KM, and LL declare no support from any organization for the submitted work: AO reports grants from Assar Gabrielsson's foundation during the conduct of the study: MB reports grants from the Swedish State under the LUA/ALF agreement and from the Heart and Lung Foundation during the conduct of the study; AO, EEB, MÅ, KM, and MB declare no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years: LL report grants from the Swedish State under the LUA/ALF agreement and the Swedish Research Council (Vetenskapsrådet) outside the submitted work: LL reports roles in the International Scientific Committee of Choices international, the board of Parker Institute, and the Scientific Advisory Committee of BIPS‐Leibniz Institute; all authors report no other relationships or activities that could appear to have influenced the submitted work. All authors confirm that they had full access to all the data in the study and accept responsibility to submit for publication.All authors have completed the ICMJE uniform disclosure form at Ethical permission for the study was obtained 2021‐11‐16 from the Swedish authority for ethical permissions, Dnr 2021–05638‐02 and 2023‐04937‐02.No consent was obtained from participants since data were retrieved from registers.Data S1.Click here for additional data file.


Identify trends in swallowing outcomes in p16+ oropharyngeal squamous cell carcinoma following neoadjuvant chemotherapy+surgery (NAC+S) versus neoadjuvant chemotherapy+surgery+radiation (NAC+S+R).Cohort study.Single academic institution.p < .05.Swallowing outcome was measured using a validated questionnaire, MD Anderson Dysphagia Inventory (MDADI). MDADI scores were compared between NAC+S and NAC+S+R groups in short‐term (<1 year), middle‐term (1‐3 years), and long‐term (>3 years). Clinical factors associated with MDADI scores were explored using a linear mixed model. Statistical significance was established at p = .002; NAC+S+R: score increase = 11.18, p = .044), long‐term compared to short‐term , and long‐term compared to middle‐term . NAC+S patients had better MDADI scores than NAC+S+R patients at short‐term . There was no significant difference in swallowing function in the middle‐term or long‐term.Sixty‐seven patients met the inclusion criteria and were divided into 2 groups: NAC+S (57 [85.1%]) and NAC+S+R (10 [14.9%]). All patients had improved MDADI scores in the middle‐term compared to short‐term (NAC+S: score increase = 3.43, Regardless of treatment type, swallowing will likely be improved in the middle‐term and long‐term compared to the short‐term. Patients treated with NAC+S+R will have worse short‐term swallowing function. However, in the middle‐term and long‐term, there is no significant difference in swallowing function between patients treated with NAC+S and NAC+S+R. Within the last 40 years, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has remarkably increased in the United States, with an estimated 54,000 new cases and 11,230 deaths in 2022.Our institution utilizes neoadjuvant chemotherapy followed by transoral robotic surgery (NAC+S) as a novel de‐escalated treatment strategy for selected HPV+ OPSCC patients. The NAC+S protocol is both systemic escalations combined with locoregional de‐escalation, scaling down the surgery by reducing the margin of primary resection, and reserving radiation for salvage only.With the advancement of treatment modality and favorable prognosis of OPSCC patients, quality of life has emerged as an important outcome measure in evaluating treatment success.We performed a cross‐sectional cohort study to evaluate swallowing outcomes among OPSCC patients. All patients who were diagnosed with HPV+ OPSCC, received NAC+S as a primary treatment at a single academic institution between January 2006 to December 2020 and completed the MDADI survey were included in this study. Patients with otherwise unclear information were also excluded from the study. Patient characteristics, tumor, and treatment details were obtained from a retrospective chart review. All patients were staged using the 7th edition American Joint Committee on Cancer (AJCC) guideline to maintain consistency as most patients received treatment prior to the release of the 8th edition guidelines. The study was approved by the George Washington University School of Medicine Institutional Review Board (NCR202928).2 and Cisplatin 75 mg/m2 every 3 weeks. Surgery was followed at least 3 weeks after the completion of NAC and was performed using a transoral robotic surgery approach with either unilateral or bilateral neck dissection. Postoperative radiation was recommended for patients with high clinical staging or the presence of at least 1 unfavorable marker found on surgical pathology, including positive margin, ENE, and PNI. In our study, the swallowing function of 2 groups of HPV+ OPSCC patients was compared based on treatment modality: NAC+S versus neoadjuvant chemotherapy+surgery+radiation (NAC+S+R).Neoadjuvant chemotherapy (NAC) was offered to the patients with HPV+ OPSCC, AJCC 7 stage III , and stage IVa , with no evidence of distant metastatic disease. NAC includes 3 cycles of taxane‐based chemotherapy consisting of Docetaxel 75 mg/mMDADI was used to assess patients' swallowing function. MDADI is a 20‐item questionnaire with responses on a 5‐point Likert scale that are converted numerically from 1 (strongly agree) to 5 (strongly disagree). It includes 1 question on global function and 19 additional questions related to the emotional, functional, and physical aspects of swallowing. A total score was calculated, ranging from 20 to 100, with higher scores indicating better swallowing function.MDADI was administered by multiple methods, including in‐person follow‐up visits, by phone, and/or by email provided from electronic records. Participation in the study was voluntary, and the patients could refuse to complete the questionnaire at any time. As MDADI was given at most of the follow‐up visits as part of the standard of care to monitor for patients' swallowing function, a patient could have multiple MDADI scores. However, MDADI was not administered at every follow‐up visit resulting in inconsistent time points for MDADI completion. Thus, MDADI scores for each patient were divided into 3‐time frames: short‐term, middle‐term, and long‐term. Short‐term is defined as MDADI completed less than 1‐year posttreatment completion. Middle‐term is defined as MDADI completed between 1 and 3 years posttreatment completion. Long‐term is defined as MDADI completed more than 3 years posttreatment completion.T test and a paired T test were performed to compare continuous measurements. The χ2 test was performed to compare the distribution of categorical data. The linear regression model was employed to build the model to predict the MDADI scores. Missing data were replaced by series means if necessary. Statistical analysis was performed using SPSS statistical software . Statistical significance was established at p < .05.An independent A total of 198 patients who were diagnosed with OPSCC at a single academic institution between January 2006 to December 2020 were identified. After excluding 59 patients with HPV negative or unknown HPV status, 3 patients with unknown treatment modality, 22 patients treated with surgery only, and 16 patients treated with radiation only, 98 patients were identified to be diagnosed with HPV+ OPSCC and underwent NAC+S as a primary treatment. Of 98 patients, 75 (76.5%) patients underwent NAC+S only and 23 (23.5%) patients underwent additional adjuvant chemoradiation. Upon excluding 31 patients without completing the MDADI survey, 67 patients were included in the study. The NAC+S group had 57 patients (85.1%), and the NAC+S+R group had 10 patients (14.9%) . The NAC+S group had more patients in T1 and N0 stages compared to the NAC+S+R group . The NAC+S group had more patients with the complete response to NAC+S with a pathology stage of T0N0 compared to the NAC+S+R group . The NAC+S+R group had more patients who underwent bilateral neck dissection compared to the NAC+S group . There was no difference in postoperative complication between the 2 groups (p = .880).Patient and tumor characteristics were compared between the NAC+S group and the NAC+S+R group in Table p = .002), at long‐term compared to short‐term , and at long‐term compared to middle‐term . Similarly, within the NAC+S+R group, the patients had better MDADI scores in the middle‐term compared to the short‐term , better MDADI score in the long‐term compared to short‐term , and better MDADI score at long‐term compared to middle‐term .Mean differences in MDADI scores during short‐term, middle‐term, and long‐term follow‐ups were compared between the NAC+S and the NAC+S+R groups Table . Within p = .001). However, there was no statistical difference in mean MDADI score between 2 groups at middle‐term and long‐term . The details of this finding are summarized in Table p < .001). However, there were no significant score differences between the 2 groups in the middle term (p = .067) . There were no significant differences in the distribution of MDADI score categories between these 2 groups in the middle term and long term. These findings are demonstrated in Figure MDADI scores were categorized into poor (<60), adequate (≥60 to <80), and optimal (≥80), and were compared between the NAC+S group and the NAC+S+R group at short‐, middle‐, and long‐term Table . The NACCurrent management for oropharyngeal carcinoma based on National Comprehensive Cancer Network guidelines is either definitive radiotherapy (with or without chemotherapy) or primary surgery  followed by adjuvant radiotherapy as indicated.Our study found several critical trends in swallowing function in the NAC+S and NAC+S+R treatment groups. First, we found that patients treated with NAC+S had significantly better swallowing function at short‐term follow‐up (<1 year) compared to the patients treated with NAC+S+R. When short‐term MDADI scores are further subclassified, patients treated with the NAC+S were significantly more likely to report optimal swallowing function (MDADI score >80) compared to the patients treated with NAC+S+R (86% vs 20%). This appears consistent with published literature, as other studies also report lower functional outcomes in patients who underwent primary chemoradiotherapy compared to those who underwent TORS with adjuvant therapy. One study reported that the patients treated with TORS and adjuvant therapy scored more than 20 points higher on MDADI assessments compared to patients treated with primary chemoradiotherapy at 12‐month follow‐up.Second, we found that patients in both groups showed improvement in swallowing function at both middle‐term (1‐3 years) and long‐term (>3 years) follow‐ups compared to the short‐term (<1 year). The swallowing function also improved in the long term (>3 years) compared to the middle term in both treatment groups. This continued improvement in swallowing function beyond 1‐year posttreatment in NAC+S patients is consistent with the reported data in the literature; patients treated with surgical techniques have been shown to have continued improvement after 1 year.p = .001), but not at middle‐term and long‐term follow‐up. Specifically, we found that long‐term average MDADI scores were nearly identical in patients treated with NAC+S vs those treated with NAC+S+R . We postulate that the persistent improvement seen in our study may be due to multiple causes. First, we believe that NAC results in a reduced extent of resection. Additionally, NAC may result in reduced radiation dosage in patients who require adjuvant radiation therapy, resulting in the preservation of long‐term swallowing function. We believe that usage of NAC results in a de‐escalation of severity at each treatment stage, which may contribute to preserved long‐term swallowing function. Although the definitive explanation and recommendations are limited due to the small sample size in the NAC+S+R group, our results demonstrate the possibility of favorable swallowing function in NAC+S cohorts regardless of adjuvant radiotherapy status. Given the established negative long‐term reduction in swallowing function caused by radiation therapy and the feared development of late‐RAD, initial treatment with NAC+S presents a possible approach to reduce the long‐term worsening in swallowing function in HPV+ OPSCC patients.Similarly, when comparing swallowing function between the NAC+S and the NAC+S+R groups, the significance was only shown at short‐term follow‐up . However, all patients followed a normal pretreatment diet, showing that patients had preserved swallowing function before treatment. This allowed us to conclude that measured MDADI scores during follow‐up were unlikely to be skewed by baseline abnormal swallowing function and further allowed us to use this study as an evaluation of how adjuvant radiation therapy changes MDADI score and swallowing function. Another limitation is the lack of standardization of follow‐up times for MDADI assessment. The timing of survey administration differed between individual patients, which may have resulted in variable distribution within short, middle, and long‐term subcategories. Also, the long‐term follow‐up time set at 3 years may be arbitrary as the extent of dysphagia at 3 years may be different than in later years for some patients. However, several other studies used a long‐term follow‐up point of 2 years and showed stable swallowing function after this time.1.Both patients treated with NAC+S and NAC+S+R have continued improvement in swallowing function at short (<1 year), medium (1‐3 years), and long (3+) term follow‐ups.2.Patients treated with NAC+S have significantly better swallowing function at short‐term follow‐up compared to patients treated with NAC+S+R.3.Swallowing function does not significantly differ at middle‐ and long‐term follow‐up between patients treated with NAC+S and NAC+S+R.We report several findings that can help establish expectations, guide patient education, and maximize long‐term swallowing function in p16+ OPSCC patients:We found that patients treated with NAC+S have significantly better short‐term swallowing function when compared to patients treated with NAC+S+R. However, long‐term swallowing scores are nearly identical when comparing the 2 treatment groups.Esther Lee, concept, design, acquisition, analysis, interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Hari Magge, concept, design, acquisition, analysis, interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Isabel Park, concept, design, acquisition, analysis, interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Leyn Shakhtour, concept, design, acquisition, analysis, interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Ning‐Wei Li, concept, design, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Jennifer Schottler, concept, design, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Arjun S. Joshi, concept, design, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Punam G. Thakkar, concept, design, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work; Joseph F. Goodman, concept, design, critical revision of the manuscript for important intellectual content, accountability for all aspects of the work.None.None.


The treatment of extensive stage small‐cell lung cancer (ES‐SCLC) has only made modest progress in the past decade, with two immune checkpoint inhibitors (ICIs), atezolizumab and durvalumab, approved for the treatment of SCLC by January 2022. However, currently, there is limited real‐world data on ES‐SCLC patients received immunotherapy.We retrospectively collected and analyzed the demographic and treatment data of ES‐SCLC patients at the First Affiliated Hospital of Guangzhou Medical University from January 2017 to January 2022. Survival and prognosis information was obtained through follow‐up.p < 0.001, and 83.03% vs. 68.09%, p < 0.001). Moreover, the progression‐free survival (PFS) and overall survival (OS) of ES‐SCLC patients receiving immunotherapy as the FL treatment were better than the chemotherapy group . Furthermore, the OS of ES‐SCLC patients who received immunotherapy as second‐line treatment was better than that in the chemotherapy group .A total of 353 ES‐SCLC patients were included, of which 165 received immunotherapy combined with chemotherapy as the first‐line (FL) treatment (chemo‐immune group), and 188 received chemotherapy (chemotherapy group). The objective response rate (ORR) and disease control rate (DCR) of patients receiving immunotherapy as the FL treatment were better than the chemotherapy group  as the FL treatment would prolong the PFS and OS in the ES‐SCLC. Chest radiotherapy with ICI administered may benefit the ES‐SCLC. ICI‐combined treatment in second/further‐line strategies might prolong the prognosis of the refractory SCLC even if patients did not receive ICI in the FL treatment. For the choice of ICIs in FL treatment for ES‐SCLC patients, PD‐1 inhibitor or PD‐L1 inhibitor cannot bring about significant differences in efficacy and safety. SCLC is characterized by rapid tumor cell proliferation, early distant metastasis, and poor prognosis.In clinical practice, SCLC is classified as limited stage (LS), where lesions are limited to one rib cage, or extensive stage (ES), where the cancer spreads to the other lung, lymph nodes on the other side of the chest, or distant organs, according to the Veterans Administration Lung Study Group (VALSG).The first immune checkpoint inhibitor (ICI), Ipilimumab (anti‐cytotoxic T lymphocyte‐associated antigen‐4), was approved for advanced melanoma in March 2011 based on the prognosis benefit in a phase III trial.In summary, the current treatment strategies in SCLC are limited, and the clinical benefits are far less than those in NSCLC. Currently, most studies on the application of ICIs in SCLC are based on clinical trials. Therefore, more relevant data on treatment patterns, efficacy, and safety in the real world is required. In addition, there is a lack of research on the efficacy and safety of ICIs as a second‐line treatment for ES‐SCLC. Hence, we reviewed the data of 353 ES‐SCLC patients in our center over the past 5 years and explored the efficacy and prognosis of ICIs for ES‐SCLC patients.22.1We retrospectively collected data on ES‐SCLC patients diagnosed and treated at the First Affiliated Hospital of Guangzhou Medical University from January 2017 to January 2022. The inclusion criteria were as follows: (I) defined pathological diagnosis of small‐cell lung cancer; (II) clinical stage of the patient is ES; (III) patients chose etoposide combined with platinum as FL chemotherapy and received at least one course of anti‐tumor therapy; and (IV) at least one measurable lesion with a single diameter . The exclusion criteria were as follows: (I) age < 18 years; and (II) incomplete demographic and treatment‐related data.2.2We divided the ES‐SCLC patients into two cohorts, the chemo‐immune group, and the chemotherapy group, according to whether they received immunotherapy in the FL treatment. Data collected included: patients' demographics and baseline characteristics ; laboratory assessment of neutrophil granulocytes, eosinophils, lymphocytes, platelets, lactate dehydrogenase, neuron‐specific enolase, sodium, interleukin‐2 (IL‐2), IL‐4, IL‐6, IL‐10, tumor necrosis factor‐α (TNF‐α), and interferon‐γ (IFN‐γ) before treatment; treatment characteristics , and immune‐related adverse events [irAEs]); and follow‐up treatments.The therapeutic effect index, including disease control rate (DCR) and objective response rate (ORR), was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression‐free survival (PFS) was defined as the time from the initiation of therapy to disease progression or death. OS was defined as the time from initial treatment to the end; the last follow‐up was November 1, 2022.The diagnostic criteria of SCLC were based on the “2015 Chinese Guidelines for the Diagnosis and Treatment of Primary Lung Cancer” and the tumor classification of patients followed the “World Health Organization Classification of Lung Tumor Tissue”.2.3p ≤ 0.1 in the univariate analysis were included in the multivariate analysis. The hazard ratio (HR) was reported along with the 95% confidence interval (CI). Kaplan–Meier survival curves were used to evaluate the PFS and OS of patients, and the log‐rank test was used to assess differences between groups. A p‐value of <0.05 indicated statistical significance for all tests. The statistical significance levels were all two‐sided. SPSS version 22.0 was used for analysis, and the graphs were generated using GraphPad Prism 8.0.2.An unpaired t‐test was used to compare continuous variables between the observation and control groups. The Chi‐squared or Fisher's exact tests were used to compare categorical variables between the two groups. Univariate and multivariate analyses were performed using Cox proportional hazards models to investigate the risk factors associated with fatal outcomes. Risk factors with 2.4Institutional review board/ethics committee approval was obtained from the Institutional Review Board of the First Affiliated Hospital of Guangzhou Medical University , which was then approved by each participating center. Furthermore, the research procedures followed the ethical standards of the responsible committee on human experimentation and were in accordance with the Helsinki Declaration of 1975.33.1p = 0.008).We included a total of 353 ES‐SCLC patients, of which 188 chose etoposide combined with platinum as the FL chemotherapy regimen for anti‐tumor treatment (chemotherapy group), and the remaining 165 chose immunotherapy combined with chemotherapy as the first‐line treatment (chemo‐immune group). ICIs for patients included sintilimab, camrelizumab, toripalizumab, tislelizumab, nivolumab, pembrolizumab (PD‐1 inhibitors); and atezolizumab and durvalumab (PD‐L1 inhibitors). Twenty‐two patients in the chemo‐immune group received two courses of induction chemotherapy before immunotherapy. The procedure for screening eligible cases is shown in Figure 3.2p < 0.001). Regarding the selection of ICIs in ES‐SCLC patients in the chemo‐immune group, 91 (55.15%) patients chose PD‐1 inhibitors, while the remaining 77 (44.85%) patients chose PD‐L1 inhibitors. The course of chemotherapy as the FL treatment in the chemo‐immune group was longer than that in the chemotherapy group . In addition, 12.73% of patients in the chemo‐immune group had irAEs; immunotherapy‐related hypothyroidism occurred the most frequently (4.85%), and 3.03% of patients developed hypothyroidism, 1.21% of patients developed dermatitis, 1.21% of patients developed enteritis, 0.61% of patients developed immunotherapy‐related myocarditis, and 0.61% of patients developed immunotherapy‐related thrombocytopenia. By the end of the follow‐up, 117 patients in the chemo‐immune group had tumor progression, and 61.54% had received second‐line treatment. Of the 145 patients in the chemotherapy group who developed tumor progression, 55.86% received second‐line therapy, and 31 chose immunotherapy monotherapy or a combination with chemotherapy as second‐line treatment , and the OS of the chemo‐immune group was better than the chemotherapy group . After the multivariate and univariate analysis of the 353 ES‐SCLC patients, we found that in addition to FL immunotherapy, poor PS score (≥2) at diagnosis and no thoracic radiotherapy were independent risk factors for poor survival and prognosis  and PD‐L1 subgroup (n = 74) according to the choice of ICIs. Treatment characteristics and prognosis of patients between PD‐1 and PD‐L1 subgroups are shown in Table p = 0.080; OS, 14.30 months vs. 12.33 months, p = 0.893). In addition, there was no statistical difference in the occurrence of treatment‐related AEs (including irAEs) between PD‐1 and PD‐L1 subgroups.We divided the 165 ES‐SCLC patients in the chemo‐immune group into the PD‐1 subgroup (3.5p = 0.609). The survival curve is shown in Figure In the chemo‐immune group, 72 patients received second‐line treatment after tumor progression. Forty‐seven chose immunotherapy as second‐line treatment, and their OS was not significantly different from other patients ; the survival curve is shown in Figure In the chemotherapy group, 81 patients received second‐line treatment after tumor progression. Furthermore, we selected 31 patients who received immunotherapy in the second‐line treatment as the immunotherapy group and the remaining 50 as the control group for subgroup analysis. The characteristics of patients between the immunotherapy group and control groups are shown in Table 4A high tumor mutation burden (TMB) and tumor cell programmed death ligand (PD‐L1) expression are associated with immunotherapy response.p = 0.007), PFS  were improved, but there was no difference in the ORR.The IMpower133 clinical trial is an international, double‐blind, randomized, placebo‐controlled phase III trial, which evaluated the efficacy and safety of FL treatment with etoposide plus carboplatin in combination with atezolizumab (anti‐PD‐L1 inhibitor) compared to chemotherapy combined with placebo in treatment‐naive ES‐SCLC. A total of 403 de novo diagnoses of ES‐SCLC were enrolled in the study. The median OS . However, the proportion of male patients was higher , with a lower proportion of smokers , and there was a higher frequency of brain metastases  in our study. In addition, compared with the previous two randomized controlled trials, our cohort included some patients with a PS score (≥2), which is the most significant difference. Furthermore, in the present retrospective real‐world study, the PFS of 5.1 months was better than that reported in the previous IMpower133 and CASPIAN trials. The OS of patients who received ICIs was consistent with that of the previous studies mentioned above, while the OS of 11.2 months in the chemotherapy alone as the FL treatment was better than the previous two trials. A better PS has been considered as an indicator related to prolonged prognosis in previous retrospective real‐world studies.p = 0.036). A previous study has shown that ICI‐combination patterns in the second‐line treatment can still be beneficial for recurrent SCLCs.In the multivariate and univariate analysis of the present study, a poor PS score (≥2) at diagnosis was found to be an independent risk factor for worse survival and prognosis. Although a certain number of poor PS score  patients were included, the OS of the patients in this study was not worse than that in the above two studies. In our chemotherapy group, 55.86% of patients received second or further line treatment strategies, and 31 of them were administered ICIs; the survival time of these patients with ICIs was still better than patients without ICIs , which were not provided in previous clinical trials. Therefore, to the best of our knowledge, this is the first study to comprehensively analyze the efficacy and safety of both PD‐1 inhibitors and PD‐L1 inhibitors combined with chemotherapy as the FL treatment in ES‐SCLC in the real world; we found that the prognosis of patients treated with PD‐1 inhibitors is not worse than patients treated with PD‐L1 inhibitors.There are some limitations in the current study. (1) As a retrospective study relying on electronic medical records and telephone follow‐up, the subjects included in this study were enrolled over a long period (the earliest time of treatment among enrolled patients was January 2017), thus leading to the assessment of inconsistent outcomes for the patient. (2) We had not recorded some important biomarkers currently considered effective predictors of immunotherapy, such as PD‐L1 and TMB; these may be critical factors for the efficacy and prognosis of patients in our study. (3) There are omissions in the records of treatment‐related AEs, mainly caused by doctors' lack of knowledge of irAEs for early immunotherapy cases; this critical information could not be completed in the follow‐up. (4) This is a real‐world study that enrolled patients over 5 years, thus, the comparison of baseline data of the two cohorts has limitations, including sex, age, and tumor metastasis.5The present study showed that ICI combined with etoposide and cisplatin chemotherapy as the FL treatment could prolong the PFS and OS of ES‐SCLC patients. Thoracic radiotherapy with ICI administration might be beneficial in ES‐SCLC; however, more prospective studies were required to explore the safety and efficacy of radiotherapy administered during immunotherapy. ICI‐combined treatment in second/further ‐line strategies might prolong the prognosis of refractory SCLC, even if patients did not receive ICI in the FL treatment. Regarding the choice of ICIs in the FL treatment for ES‐SCLC patients, PD‐1 inhibitors or PD‐L1 inhibitors did not show significant differences in efficacy and safety.Guihuan Qiu: Conceptualization (lead); formal analysis (lead); methodology ; writing – original draft (lead). Fei Wang: Conceptualization ; data curation ; formal analysis (lead); writing – original draft (lead). Xiaohong Xie: Conceptualization ; data curation ; investigation (lead); writing – original draft (supporting). Ting Liu: Data curation (supporting); formal analysis (supporting); investigation (lead); methodology (supporting); resources (supporting). Chen Zeng: Methodology (lead); software (supporting); validation (supporting); visualization (supporting). Ziyao Chen: Data curation (supporting); investigation ; resources (lead); validation (supporting); visualization (supporting). Maolin Zhou: Methodology ; resources (lead); software . Haiyi Deng: Methodology (lead); resources ; software (supporting); supervision (supporting). Yilin Yang: Funding acquisition ; investigation (supporting); software (lead); supervision (supporting). Xinqing Lin: Investigation ; visualization (supporting); writing – original draft (supporting). Zhanhong Xie: Resources (supporting); supervision (supporting); validation (supporting); visualization (supporting). Gengyun Sun: Formal analysis (supporting); resources (supporting); validation ; visualization (supporting). Chengzhi Zhou: Conceptualization (supporting); funding acquisition (lead); project administration (lead); writing – original draft (supporting); writing – review and editing . Ming Liu: Conceptualization (supporting); funding acquisition ; resources (lead); visualization (lead); writing – original draft ; writing – review and editing (lead).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.This study was supported by grants from Chinese Society of Clinical Oncology [Y‐HS202102‐0118]; State Key Laboratory of Respiratory Disease‐The Independent project [2020GIRH007]; Zhijiang Laboratory‐The open project [2021PE0AC06].This study was approved by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University . Study was performed in accordance with the ethical standards of the Declaration of Helsinki. There was no additional invasive test or experimental drugs used out of order for the patients.The patients/participants provided their written informed consent to participate in this study.NA.NA.Figure S1.Figure S2.Figure S3.Figure S3.Figure S4.Figure S5.Click here for additional data file.Table S1.Table S2.Click here for additional data file.


Social anxiety disorder (SAD) and major depressive disorder (MDD) are both associated with diminished global positive affect. However, little is known about which specific positive emotions are affected, and which positive emotions differentiate MDD from SAD.N = 272): control group , SAD without MDD group (n = 76), MDD without SAD group (n = 46), and comorbid group . Discrete positive emotions were measured with the Modified Differential Emotions Scale, which asked about the frequency of 10 different positive emotions experienced during the past week.Four groups of adults recruited from the community were examined (The control group had higher scores on all positive emotions compared to all three clinical groups. The SAD group had higher scores on awe, inspiration, interest, and joy compared to the MDD group, and higher scores on those emotions, as well as amusement, hope, love, pride, and contentment, than the comorbid group. MDD and comorbid groups did not differ on any positive emotions. Gratitude did not differ significantly between clinical groups.Adopting a discrete positive emotion approach revealed shared and distinct features across SAD, MDD, and their comorbidity. We consider possible mechanisms underlying transdiagnostic vs. disorder-specific emotion deficits.The online version contains supplementary material available at 10.1007/s10608-023-10355-y. Social anxiety disorder (SAD) and major depressive disorder (MDD) are common mental health conditions that lead to impairment in social and occupational functioning  Do individuals with SAD, MDD, or both SAD and MDD experience specific positive emotions less often than individuals without a history of an anxiety or depression diagnosis? and (2) Does the frequency of positive emotion experiences differ across individuals with SAD, MDD, or comorbid SAD and MDD? Based on Cohen & Huppert  and GrubThe sample included 272 participants recruited from the community for four previously conducted clinical trials and one cross-sectional study. These trials selected for individuals with either 1) a current principal diagnosis of SAD (NCT02136212) or (2) a current principal diagnosis of MDD  current pharmacological treatment for anxiety or depression , (2) concurrent psychotherapy unless 12 week stability criteria had been met, (3) current active suicidal ideation with intent, (4) history of a major neurological disorder or moderate to severe traumatic brain injury, (5) moderate or severe alcohol or marijuana use within the past year, or mild or greater substance use disorder of all other drugs within the past year, (6) bipolar I or psychotic disorders, and (7) characteristics that may compromise MRI safety .n = 76); 16.9% of individuals with a MDD principal diagnosis and no SAD diagnosis (n = 46); 27.2% individuals with SAD and MDD comorbid diagnoses (n = 74); and 27.9% individuals in the control group (n = 76). The demographics of this sample were: age , years of education , gender , race , ethnicity (22.1% Hispanic), and race and ethnicity combined for cultural heritage ; MDD principal diagnosis, no SAD (n = 46); SAD and MDD comorbid (n = 74); and the control group (n = 76).A multivariate analysis of variance (MANOVA) was conducted to examine group differences in positive emotions. The dependent variables were the 10 positive emotions from the mDES. Univariate tests were examined for each discrete positive emotion pending a significant omnibus diagnostic group effect. Tukey’s HSD was used to compare positive emotions between groups as follows: SAD principal diagnosis, no MDD  = 7.523, p = .275), ethnicity (X2(3) = 3.060, p = .382), and race (X2(21) = 30.325, p = .086) did not differ significantly across groups. Age differed such that the MDD only group was older than the control, SAD only, and comorbid groups  = 5.537, p = .001). Years of education also differed such that the control group had more years of education than the MDD only and comorbid groups, and the SAD only group had more years of education than the comorbid group  = 7.941, p < .001). See Table Gender  = 245.026, p < .001) such that all clinical groups had higher scores than the control group, and the comorbid and SAD only groups had greater scores than the MDD only group; scores did not differ significantly between the SAD only and comorbid groups. BDI-II scores also differed between groups  = 176.653, p < .001). Comorbid and MDD only groups had higher BDI-II scores than the SAD only and control groups, and the SAD group had a greater score than the control group. The comorbid and MDD only groups’ scores did not differ significantly. See Table LSAS scores differed between the groups  = 13.566, p < .001; Wilk’s Λ = 0.284; ηp2 = 0.342). See Table p < .05). The comorbid group experienced amusement, awe, hope, inspiration, interest, joy, love, pride, and contentment less than the SAD only group, and the MDD only group experienced awe, inspiration, interest, and joy less than the SAD only group . The MDD only and comorbid groups did not differ across any positive emotion . Gratitude was the only positive emotion not to significantly differ between clinical groups. See Table The main analysis revealed that positive emotions differed across SAD only, MDD only, comorbid, and control groups (p < .001). When controlling for depression, amusement, gratitude, and interest no longer correlated with social anxiety . When controlling for social anxiety, all positive emotions still correlated with depression . See Supplemental Table 2 for correlations. See Supplemental Fig. 1 and Supplemental Fig. 2 for frequency distributions of LSAS and BDI-II scores.All positive emotions had significant negative correlations with LSAS and BDI-II scores  = 1.391, p = .122; Wilk’s Λ = 0.881; ηp2 = 0.061). Race and ethnicity also did not interact significantly with diagnostic groups, meaning cultural heritage did not impact the effect of diagnostic group on positive emotions  = 0.849, p = .787; Wilk’s Λ = 0.792; ηp2 = 0.038). These results should be interpreted cautiously because cultural heritage groups were created post hoc and differed significantly across diagnostic groups (X2(6) = 13.826, p = .032). See Table Positive emotions did not differ across combined race and ethnicity  primarily serve social functions. Gratitude is a response to unexpected benefits due to another person’s actions, and it motivates individuals to express kindness and generosity to others . Amusement is associated with opportunities for humor and play . Inspiration is an emotion that pushes people to challenge themselves and to grow (Algoe & Haidt, The secondary dimensional analyses largely converged with the primary results. All positive emotions significantly correlated with both depression and social anxiety. When accounting for shared variance in symptoms, all positive emotions remained correlated with depression after controlling for social anxiety; in contrast, amusement, gratitude, and interest no longer significantly correlated with social anxiety after controlling for depression. These findings further suggest that overall deficits in positive emotions may be associated with depression, whereas social anxiety appears to be characterized by specific positive emotion deficits. Further research is needed on the association between discrete positive emotions and continuous measures of social anxiety and depression, as participants in this study were recruited for distinct diagnostic groups as opposed to dimensional symptomology.Overall, the findings are largely consistent with previous studies (Cohen & Huppert, The exploratory analyses indicated that culture did not interact with diagnosis nor contribute to differences in positive emotions. Further investigation is needed, since participants were not recruited with these characteristics in mind. Race and ethnicity alone do not wholly reflect culture, and Hispanic and Latin heritage are not synonymous with each other. There are also other cultural aspects that may interact with diagnosis and positive emotions, such as degree of acculturation and identification with one’s native culture, or the desirability and appropriateness of certain emotions in different communities (Koneru et al., Beyond cultural considerations, using the mDES to measure emotions has other limitations. It utilizes single-item, self-report ratings, and therefore requires individuals to identify and communicate their emotions. Since there are ways to process emotion other than verbally (e.g., somatically; Villanueva et al., Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3Supplementary Material 4


Umbilical cord blood gases are routinely used by midwives and obstetricians for quality assurance of birth management and in clinical research. They can form the basis for solving medicolegal issues in the identification of severe intrapartum hypoxia at birth. However, the scientific value of veno-arterial differences in cord blood pH, also known as ΔpH, is largely unknown. By tradition, the Apgar score is frequently used to predict perinatal morbidity and mortality, however significant inter-observer and regional variations decrease its reliability and there is a need to identify more accurate markers of perinatal asphyxia. The aim of our study was to investigate the association of small and large veno-arterial differences in umbilical cord pH, ΔpH, with adverse neonatal outcome.This retrospective, population-based study collected obstetric and neonatal data from women giving birth in nine maternity units from Southern Sweden from 1995 to 2015. Data was extracted from the Perinatal South Revision Register, a quality regional health database. Newborns at ≥37 gestational weeks with a complete and validated set of umbilical cord blood samples from both cord artery and vein were included. Outcome measures included: ΔpH percentiles, ‘Small ΔpH’ (10th percentile), ‘Large ΔpH’ (90th percentile), Apgar score (0–6), need for continuous positive airway pressure (CPAP) and admission to neonatal intensive care unit (NICU). Relative risks (RR) were calculated with modified Poisson regression model.P = 0.01; CPAP 0.55, P = 0.02; NICU admission 0.81, P = 0.01). ‘Small ΔpH’ was associated with an increased RR for low Apgar score and NICU admission only at higher UApH values .The study population comprised of 108,629 newborns with complete and validated data. Mean and median ΔpH was 0.08 ± 0.05. Analyses of RR showed that ‘Large ΔpH’ was associated with a decreased RR of adverse perinatal outcome with increasing UApH  at birth were associated with a lower risk for perinatal morbidity including low 5-minute Apgar Score, the need for continuous positive airway pressure and NICU admission when UApH was above 7.15. Clinically, ΔpH may be a useful tool in the assessment of the newborn’s metabolic condition at birth. Our findings may stem from the ability of the placenta to adequately replenish acid-base balance in fetal blood. ‘Large ΔpH’ may therefore be a marker of effective gas exchange in the placenta during birth.The online version contains supplementary material available at 10.1186/s12884-023-05487-8. Umbilical cord blood gases are the most objective measure of the newborn’s metabolic condition at birth –3. SustaFor the identification of an accurate UApH value, it is important to obtain a correct cord venous pH (UVpH) , and altDelta pH is widely recognized in the clinical setting, but only a handful of studies have attempted to demonstrate its association with fetal outcomes. A small study evaluating the relationship of ΔpH to cardiotocography patterns found no relation between large ΔpH and acute onset acidemia . Belai aUsing a large, population-based cohort, we aimed to explore the association of veno-arterial differences in cord pH (i.e. the difference between UVpH and UApH), namely ΔpH, with adverse neonatal outcome.Data was retrieved from the prospectively collected Perinatal Revision South Register, a quality database collecting obstetric and neonatal data from nine hospitals in Southern Sweden between 1995 and 2015. The original dataset comprised of 315,174 singleton live births with information regarding maternal characteristics, birth, perinatal outcomes, and neonatal course. Since some records from the Perinatal Revision South Register database did not contain complete sets of UApH and UVpH values, the material was supplemented with blood gas data extracted from the maternity records at Skåne University Hospital in Malmö , which is the largest maternity unit in Southern Sweden.Only newborns with a complete set of umbilical cord blood samples from both the artery and vein were included in the study. ΔpH was calculated using the equation:N = 108,629) ’ and ‘multipara, with previous CS’. Similarly, births that were reported to start as CS, but without specified mode of delivery, were regarded as elective CS. Gestational duration was classified term (37 + 0 to 40 + 6 weeks) and (41 + 0 to 41 + 6 weeks) and post-term (≥42 weeks). Birthweight was classified into four groups .In order to study the percentile distribution of ΔpH in relation to changes in cord arterial pH, we divided UApH into six classes Table . PercentStatistical analyses were performed with SPSS data software (26) . Background characteristics were calculated and distributions between parameters were compared with Pearson Chi-2-test. The distribution of ΔpH across the population was illustrated by histogram to investigate normality and percentile distribution of ΔpH in different UApH groups. Modified Poisson regression model with 95% confidence intervals (CI) was used for RR of adverse neonatal outcomes.The selection of newborns for inclusion in the study is illustrated in Fig. N = 108,629) and for UApH classes. The mean ΔpH decreased with rising UApH, from 0.13 in pH < 7.00 to 0.07 in pH ≥7.20 and varied within each percentile.The distribution of ΔpH across the study population is illustrated in Fig. P = 0.01); and at UApH ≥7.20, the RR was 1.65 (95%CI = 1.26–2.1) (P < 0.00). In contrast, a lower relative risk was found for ‘Large ΔpH’ for Apgar 0–6 at 5 minutes. At UApH 7.15–7.199, the RR was 0.48 (95%CI = 0.27–0.84) (P = 0.01). This apparent protective effect was enhanced for UApH ≥7.20, where the RR for Apgar 0–6 was 0.29 (95%CI = 0.12–0.71) (P = 0.01). These changes are illustrated in Fig. In Table P = 0.048) and NICU admission (P = 0.01); and at UApH ≥7.20 for CPAP (P = 0.02) and NICU admission (P = 0.01).Of interest, ‘Large ΔpH’ showed the same protective trend at UApH 7.15–7.199 from need of CPAP  with adverse neonatal outcome and found that large differences between umbilical cord venous and arterial pH (‘Large ΔpH’) were strongly associated with a lower relative risk for Apgar < 7 at 5 minutes, need for CPAP and NICU admission. These changes were strongest for infants born without acidemia.As oxygen, carbon dioxide and hydrogen ions readily diffuse across the placenta to the maternal side for elimination, the fetus is dependent on adequate placental function in order to maintain its acid-base balance . This deClinically, most cases of fetal acidosis are acute in onset and are accompanied by large veno-arterial differences in pH (i.e. ‘Large ΔpH’). This is because the extracellular placental compartment has not had enough time to become saturated with acids from the fetus, or cord occlusion or fetal bradycardia have prevented fetal acids from being transferred to the placenta , 25, 26.Earlier studies have investigated the role of different cord blood gas parameters in predicting perinatal outcomes. Knutzen et al.  found thN = 33) to normal labors, found large differences between UVpH and UApH but the Apgar score was not affected. Different outcomes have been observed for acute versus the chronic acidosis, as seen by Bobrow et al. [It is well known that umbilical cord pH analysis gives a picture of the metabolic state of the newborn at birth, but previous studies have presented conflicting data. Martin et al.  in a smaw et al. , where cw et al. .Our data showed that a ‘Large ΔpH’ was associated with decreased risk for adverse neonatal outcome, yet only 1 % of the cases with the lowest Apgar score had a ‘Small’ or ‘Large ΔpH’.N = 83). Similarly, Belai et al. [Whilst reviewing the literature, only a handful studies were found to have investigated the prognostic value and clinical significance of veno-arterial differences in cord pH –10, 29 wThe major strengths of the current study stem from the large sample size and the meticulous validation of paired umbilical cord blood pH values. As small ΔpH may occur physiologically , cut-offLarge ΔpH was associated with a lower risk for neonatal morbidity including low 5-minute Apgar score, the need for CPAP and NICU admission when UApH was above 7.15. Reference values for ∆pH, including stratification of percentile values according to UApH, were reported. Our findings may have important clinical implications in the assessment of the metabolic state of the newborn at birth. They may stem from the positive effects of maintained placenta function during birth and the ability of the placenta to adequately replenish acid-base balance in fetal blood leading to a large veno-arterial differences in cord blood pH. A ‘Large ΔpH’ may therefore be a marker of effective gas exchange in the placenta during birth. Further studies are warranted to investigate changes in ΔpH in correlation to carbon dioxide and oxygen levels in umbilical cord blood gases to verify this hypothesis.Additional file 1. Correlation of ΔpH decentiles to relative risk of 5-minute Apgar score 0–6.


Diazoxide is a powerful cardioprotective agent that activates mitochondrial ATP-dependent K-channels and stimulates mitochondrial respiration. Diazoxide reduced infarct size in isolated rodent heart preparations and upon pretreatment in juvenile pigs with coronary occlusion/reperfusion. We aimed to study the use of diazoxide in a more realistic adult pig model of reperfused acute myocardial infarction when diazoxide was administered just before reperfusion.−1 diazoxide (n = 5) or placebo (n = 5) intravenously over 10 min and subjected them to 60 min coronary occlusion and 180 min reperfusion; blood pressure was maintained by use of an aortic snare. The primary endpoint was infarct size (triphenyl tetrazolium chloride staining) as a fraction of area at risk; no-reflow area (thioflavin-S staining) was the secondary endpoint. In a second approach, diazoxide (n = 5) was given from 50 to 60 min coronary occlusion, and blood pressure was not maintained. There was a significant reduction in infarct size (22% ± 11% of area at risk with diazoxide pretreatment vs. 47% ± 11% with placebo) and area of no-reflow (14% ± 14% of infarct size with diazoxide pretreatment vs. 46% ± 20% with placebo). With diazoxide from 50 to 60 min coronary occlusion, however, there was marked hypotension, and infarct size (44% ± 7%) and area of no-reflow were not reduced (35% ± 25%).In a first approach, we pretreated anaesthetised adult Göttingen minipigs with 7 mg kgCardioprotection by diazoxide pretreatment was confirmed in adult pigs with reperfused acute myocardial infarction but is not feasible when diazoxide is administered in a more realistic scenario before reperfusion and causes hypotension. Cardioprotection is characterised by reduced infarct size and reduced coronary microvascular obstruction . InfarctATP) and the release of reactive oxygen species (ROS)  . There aerfusion , 20. Alserfusion , 22. Theerfusion . In facterfusion . Oxidatierfusion . Also, terfusion . Diazoxinclamide , 26 and ecanoate , 22. Theecanoate  and creaecanoate . Also, tecanoate , 30. Howecanoate  but not ecanoate ; thus, tecanoate , when diecanoate ; and (2)Unless otherwise specified, materials were obtained from Sigma-Aldrich .The experimental protocols were approved by the Bioethical Committee of the district of Düsseldorf (G1868/21) and conform to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes. We followed the ARRIVE 2.0 guidelines , 36 and in vivo experimental model in pigs replicates many aspects of the human reperfused myocardial infarction, notably its temporal and spatial development  with straw-bedding at 12 h/12 h light/dark cycles. There was a daily visual inspection of pigs’ health by animal caretakers and veterinarians. All behavioural abnormalities were recorded and monitored; only inconspicuous, apparently healthy pigs were included in the experiment. Pigs were 17 ± 5 months and weighed 36 ± 9 kg. Pigs were sedated with flunitrazepam (i.m.: 0.4 mg kg−1). Anaesthesia was induced with etomidate  and sufentanil . Anaesthesia was maintained with isoflurane  during artificial ventilation with room air . Muscle relaxation during electrosurgery was induced with a single bolus of rocuronium . This anaesthetic regimen is identical to that used in our institution for patients undergoing surgical coronary revascularisation . Fluorescent dye was resolved from microspheres and quantified in a spectrophotometer . Blood flow was calculated as blood flow per tissue mass.Coloured microspheres were recovered from transmural myocardial samples taken from the central area at risk by digestion with 4 mol L−1 sodium phosphate buffer containing 8% dextran, Roth, Karlsruhe, Germany). The TTC-stained slices were again photographed, and transferred together with the tissue areas that remained unstained by TTC to the same transparent film that was used to document the area at risk and the no-reflow areas. Particular care was taken to proper realign the slices using “landmarks,” such as the position of papillary muscles and the incisions surrounding the no-reflow areas.Thirty millilitres of warm 4% thioflavin-S solution  was filtered through a 0.2 µm syringe-filter to remove particulate debris and slowly infused into the left atrium to demarcate non-perfused areas of the left ventricle after 180 min reperfusion , 42. TheThe transparent films were scanned and analysed using digital planimetry. The following areas were calculated and averaged for both sides of each slice: total area of the left ventricle, the area at risk, the area of TTC-negative tissue (infarcted), and the area of thioflavin-S-negative tissue within the infarcted tissue (no-reflow). Using the slice weight for normalisation, the tissue masses for the area at risk, the no-reflow area, and for the infarcted area were calculated. In addition, the area at risk was calculated as a fraction of the left ventricle, infarct size was calculated as a fraction of the area at risk, and the area of no-reflow was calculated as a fraction of infarct size.Pigs were randomised  to an I/R diazoxide pretreatment or diazoxide before reperfusion protocol, respectively.−1, atrial pacing was performed. After stabilisation for at least 30 min, systemic haemodynamics and regional myocardial blood flow were measured. After intravenous infusion of unfractionated heparin , the LAD was occluded distal to its second diagonal branch using a microvascular clamp . Heparin  was again given at 25 and 55 min coronary occlusion. At 5 and 55 min coronary occlusion, systemic haemodynamics and regional myocardial blood flow were measured again. Reperfusion was induced after 60 min coronary occlusion by quick removal of the vascular clamp and visually confirmed by the reappearance of red colour on the surface of the reperfused myocardium. Systemic haemodynamics were again measured at 10 and 180 min reperfusion and regional myocardial blood flow at 10 and 180 min reperfusion. Ventricular fibrillation during ischaemia or reperfusion, as identified from the continuous lead II ECG recording, was immediately terminated by intra-thoracic defibrillation . We did not use any antiarrhythmic or inotropic agents during resuscitation since they might interfere with the infarction process and/or cardioprotection. At the end of the experiment, pigs were euthanised by intracardiac injection of 20 ml potassium chloride (1 mol L−1).When the heart rate at baseline was <95 min−1 i.v. over 10 min in the solvent solution of 10 ml NaCl, B. Braun with 20% 1 mol L−1 NaOH, pH = 11.7) was administered after baseline measurements before ischaemia. The dose of diazoxide was determined with reference to prior studies  was administered after 50 min coronary occlusion over 10 min just before reperfusion. In this set of experiments, LVP was not adjusted with the aortic snare.The experimental protocol was identical to that of I/R, except that diazoxide  and to identify potential outliers. Data are presented as mean ± SD; individual data on infarct size and no-reflow are also presented as scatterplots. Statistical package SAS 9.4  was used to analyse haemodynamic and regional myocardial blood flow data by two-way analysis of variance  for repeated measures. Data on area at risk, infarct size, area of no-reflow, and episodes with fibrillation/defibrillation were analysed by one-way analysis of variance. When analysis of variance indicated a significant main effect or interaction, Fisher’s least square difference (LSD) tests were used for comparison of single mean values. The data and statistical analysis comply with the recommendations on experimental design and analysis in pharmacology.At baseline, heart rate, LVP, regional myocardial blood flow, and area at risk were not different between the three groups of I/R without or with diazoxide pretreatment or diazoxide just before reperfusion, respectively . With thInfarct size with I/R was 47% ± 11% of area at risk, and area of no-reflow was 46% ± 20% of infarct size; thus, both were very close to our prior data in this model . Diazoxiper se, no longer reduced infarct size and area of no-reflow. In fact, in a single extreme case, the loss of coronary perfusion pressure caused such pronounced microvascular obstruction that the washout of NADH oxidase and reducing NADH equivalents was delayed to an extent that TTC staining remained positive. These data clearly indicate that systemic administration of diazoxide before reperfusion could not induce cardioprotection, but in fact rather caused haemodynamic complications. Apart from the deleterious role of severe hypotension per se, the decrease in perfusion pressure and further decrease in regional myocardial blood flow will also have decreased the diazoxide delivery to the ischaemic myocardium. Theoretically then, one would attempt intracoronary administration of diazoxide before or at reperfusion. Unfortunately, however, diazoxide is poorly soluble (product information Sigma-Aldrich GCY/NSB 12/03)  , requiriB 12/03) , 46 or dB 12/03) , and thuB 12/03) , and thaB 12/03) –52.ATP and respiration, but unfortunately it is not feasible for translation into a realistic clinical setting of acute myocardial infarction (We must, therefore, conclude that diazoxide is a powerful cardioprotectant with an action on mitochondrial Kfarction . Mechanifarction , which dfarction . Unfortufarction , perfusifarction .


Subjects were matched (p > 0.05) based on age, height, weight, % body fat, sex, and race . There was no difference between non‐consumers and aspirin consumers for computed tomography‐determined muscle size of the quadriceps  or hamstrings , or quadriceps muscle strength . However, muscle attenuation  was higher in the aspirin consumers in the quadriceps  and hamstrings . These cross sectional data suggest that chronic aspirin consumption does not influence age‐related skeletal muscle atrophy, but does influence skeletal muscle composition in septuagenarians. Prospective longitudinal investigations remain necessary to better understand the influence of chronic COX regulation on aging skeletal muscle health.Aspirin is one of the most commonly consumed cyclooxygenase (COX)‐inhibitors and anti‐inflammatory drugs and has been shown to block COX‐produced regulators of inflammation and aging skeletal muscle size. We used propensity score matching to compare skeletal muscle characteristics of individuals from the Health ABC study that did not consume aspirin or any other COX‐inhibiting drugs ‐inhibitors and anti‐inflammatory drugs and has been shown to block COX‐produced regulators of inflammation in human skeletal muscle. Considering the negative association between inflammation and muscle mass in older individuals, data from large scale observational studies of aging may provide insight into the role of aspirin in the control of age‐related skeletal muscle atrophy. These cross sectional data suggest that chronic aspirin consumption does not influence age‐related skeletal muscle atrophy, but does influence skeletal muscle composition in septuagenarians. Previous reports from Health ABC have indicated a large prevalence of anti‐inflammatory drug use in this cohort , and Memphis, Tennessee (n = 1548). Baseline information regarding demographics, medical history, and current health status was collected during an in‐home interview between April 1997 and May 1998. Annual clinic visits included anthropometric measurements, a comprehensive inventory of current medications and supplements, and evaluation of body composition using CT and dual energy x‐ray absorptiometry (DXA). If a participant did not have valid CT data or were missing records of their medication use, they were excluded from the current investigation. All participants signed an informed written consent which was approved by the Institutional Review Boards of the University of Pittsburgh and the University of Tennessee in accordance with the Declaration of Helsinki. The current investigation was also approved by the Institutional Review Board at Ball State University.To be eligible for the Health ABC Study, participants had to report no difficulty walking at least one quarter mile and climbing 10 stairs without resting, no difficulty performing basic activities of daily living, no need for a cane, walker, crutches, or other assistive ambulatory equipment, no history of cancer treatment in the preceding 3 years, and no plan to move out of the area in the next 3 years. Health ABC aimed to recruit participants who were between 70 and 79 years of age resulting in an initial cohort of 3075 Black and White men and women. Participants in this cohort were recruited from Pittsburgh, Pennsylvania  were recorded. Participants were also asked when they began taking each drug. Drug names were matched with the Iowa drug information service (IDIS), a hierarchical coding system which categorizes pharmaceutical ingredients  and attenuation of the mid‐thigh muscles were measured by CT  as previously described in detail . Participants who did not consume aspirin or any other COX‐inhibiting drug  were classified as non‐consumers (n = 1155). These groups of aspirin consumers and non‐consumers were then considered eligible for propensity score matching  consumed aspirin on a daily basis, (2) consumed aspirin for at least 1 year leading up to their CT scan for muscle mass determination and (3) did not consume any other COX‐inhibiting drug  were classified as aspirin consumers  between groups were made using a three‐way analysis of covariance  controlling for site. Because chronic daily aspirin consumption is widely used for prevention of cardiovascular disease . Matching variables between groups were compared with a 3While the original goal was simply to capture participants with at least 1 year of aspirin consumption, the aspirin consuming cohort had a much longer average duration of aspirin use (6 year). In fact, approximately one‐third of participants (35%) had been consuming aspirin for six or more years Figure . The absp < 0.05) between men and women, and White and Black participants for quadriceps  and hamstrings  skeletal muscle size, as has been previously shown in the larger Health ABC cohort  between the non‐consumers and aspirin consumers (Table p < 0.05) between the non‐consumers and aspirin consumers (Table There were differences (p > 0.05) between the non‐consumers and aspirin consumers for quadriceps (103.2 ± 0.9 vs. 105.2 ± 0.9 cm2) and hamstrings (54.5 ± 0.5 vs. 54.9 ± 0.5 cm2) skeletal muscle size when CVD was considered. The results were also unchanged for skeletal muscle attenuation and strength, and IL‐6 levels when CVD was considered. There were no significant (p > 0.05) interactions between aspirin and the other main factors (sex and race) in any of the ANCOVAs for these variables.There was also no difference , a ubiquitin ligase contributing to muscle proteolysis, and the pleiotropic cytokine IL‐6  may not be as effective for older individuals (>70 year), like the individuals in Health ABC, because they were on the steepest part of the aging and skeletal muscle atrophy curve, at least as it has been defined for the quadriceps  and other interventions  alone or in combination. Measurements should span from whole muscle and myocellular size and function to the underlying metabolic and cellular regulation while considering sex, race, various ages, and different muscle groups.Conception and design of research: William A. Fountain, Masatoshi Naruse, W. Holmes Finch, Alex Claiborne, Scott W. Trappe, Todd A. Trappe. Analyzed data: William A. Fountain, Masatoshi Naruse, W. Holmes Finch, Todd A. Trappe. Interpreted results of experiments: William A. Fountain, Masatoshi Naruse, W. Holmes Finch, Todd A. Trappe. Prepared figures: William A. Fountain, Masatoshi Naruse, Todd A. Trappe. Drafted manuscript: William A. Fountain, Masatoshi Naruse, Alex Claiborne, Todd A. Trappe. Edited and revised manuscript: William A. Fountain, Masatoshi Naruse, W. Holmes Finch, Alex Claiborne, Scott W. Trappe, Todd A. Trappe. Approved final version of manuscript: William A. Fountain, Masatoshi Naruse, W. Holmes Finch, Alex Claiborne, Scott W. Trappe, Todd A. Trappe.This research was supported by National Institute on Aging (NIA) Contracts N01‐AG‐6‐2101; N01‐AG‐6‐2103; N01‐AG‐6‐2106; NIA grant R01‐AG028050, and NINR grant R01‐NR012459. This research was funded in part by the Intramural Research Program of the NIH, National Institute on Aging.No conflicts of interest, financial or otherwise, are declared by the authors.


SARS‐CoV‐2 genomic surveillance is necessary for the detection, monitoring, and evaluation of virus variants, which can have increased transmissibility, disease severity, or other adverse effects. We sequenced 330 SARS‐CoV‐2 genomes during the sixth wave of the COVID pandemic in Iran and compared them with five previous waves, for identifying SARS‐CoV‐2 variants, the genomic behavior of the virus, and understanding its characteristics.After viral RNA extraction from clinical samples collected during the COVID‐19 pandemic, next generation sequencing was performed using the Nextseq and Nanopore platforms. The sequencing data were analyzed and compared with reference sequences.In Iran during the first wave, V and L clades were detected. The second wave was recognized by G, GH, and GR clades. Circulating clades during the third wave were GH and GR. In the fourth wave, GRY , GK (delta variant), and one GH clade (beta variant) were detected. All viruses in the fifth wave were in GK clade (delta variant). In the sixth wave, Omicron variant (GRA clade) was circulating.Genome sequencing, a key strategy in genomic surveillance systems, helps to detect and monitor the prevalence of SARS‐CoV‐2 variants, monitor the viral evolution of SARS‐CoV‐2, identify new variants for disease prevention, control, and treatment, and also provide information for and conduct public health measures in this area. With this system, Iran could be ready for surveillance of other respiratory virus diseases besides influenza and SARS‐CoV‐2. They are not vital for viral replication; however, they are involved in pathogenesis.Coronaviruses are biologically diverse and mutate rapidly.The gold standard for monitoring and identifying new variants in SARS‐CoV‐2 is whole genome sequencing (WGS) using next generation sequencing (NGS). All SARS‐CoV‐2 genes can be sequenced using this method, including those encoding non‐structural proteins and other regions.22.1This study was a population‐based cross‐sectional assessment of data on 330 throat swabs of COVID‐19 confirmed cases from all over Iran during the sixth wave of COVID‐19, which were sent to the National Influenza Center (NIC), Department of Virology, School of Public Health, Tehran University of Medical Sciences, Iran, for whole genome sequencing of SARS‐CoV‐2 strains. These samples included inpatients and outpatients from health centers and hospitals across the country. They were chosen randomly following primary detection by Real‐time PCR based on having the ct values of below 25.2.2Viral RNA was extracted using the High Pure Viral Nucleic Acid kit . For library preparation and NGS performance, two platforms were used: Illumina and Oxford Nanopore Technologies. For Illumina platform, the Nextera DNA Flex kit  and the Respiratory Virus Oligo Panel kit  were used for library preparation and hybridization. After clean‐up, quality control evaluation was done using Qubit . At last, sequencing was performed utilizing NextSeq 550 machine .For Nanopore platform, PCR tiling of SARS‐CoV‐2 virus with rapid barcoding and Midnight RT‐ PCR Expansion (SQK‐RBK110.96 and EXP‐MRT001) (Version: MRT_9127_v110_revM_14Jul2021) was used. The library was prepared by the Rapid Barcoding Sequencing (SQK‐RBK004) kit (Version: RBK_9054_v2_revX_14Aug2019) from Oxford Nanopore Technologies®, UK. The library concentration was measured using the Qubit HS dsDNA assay kit . Finally, the sequencing was done by the GridION with the R9.4.1 flow cells .2.3All the reads were mapped to the SARS‐CoV2 reference genome assembly for data investigation. The assembled viral genome was of high quality and contained no unknown nucleotides. The gathered genomes were studied by CoVsurver mutations Application in GISAID and aligned using the sequence alignment program BioEdit. Finally, all sequences were submitted in GISAID.3In this study, 330 COVID‐19 confirmed cases from the sixth wave of COVID‐19 in Iran were subjected to NGS. These specimens were oropharyngeal swabs collected from all over the country. The period of sample collection was from March 6, 2022, to March 20, 2022. Out of 330 samples, 143 (43.3%) were female and 187 (56.7%) were male. The age ranged from younger than under 1‐year‐old to 113 years old. All of evaluated SARS‐CoV‐2 strains in the sixth wave were Omicron, in which, out of all 330 strains, 153 (46.3%) were BA.1, 159 (48.2%) were BA.2 and 18 (5.5%) were mixed lineage (ML). We analyzed amino acid (aa) substitutions, insertions and deletions of each protein separately compared to hCoV‐19/Wuhan/WIV04/2019 in GISAID. Then SARS‐CoV‐2 variants and amino acids changes in structural, non‐structural and accessory proteins were compared with SARS‐CoV‐2 strains circulated in Iran during the first five waves which were evaluated in our previous study.Amino acids changes in structural proteins were listed in Table 4As an RNA virus, SARS‐CoV‐2 has a high rate of mutations, resulting in ongoing evolution over time that could affect replication, infectivity, transmissibility, virulence, and immunogenicity.Since the development of the SARS‐CoV‐2 infection in December 2019, a few VOCs have arisen and quickly spread with a worldwide circulation.The Omicron subvariants have shown notable changes regarding S protein mutants, especially in the N‐terminal area and the receptor‐binding domain, which are known to contain important neutralizing antibody epitopes.There are 31 mutations in spike of BA.2 and 34 in BA.3, with 21 shared mutations among all.Omicron has 40 mutations including more than 30 mutations in protein S, one mutation in protein E, three mutations in protein M, and six mutations in protein N.In the Wuhan reference strain, an A‐to‐G nucleotide mutation occurred at position 23 403 and resulted in the spike D614G amino acid change, which was detected in early March 2020.The N501Y mutation is localized to the RBD and helps in achieving higher binding affinity to host cells, potentially leading to increased transmission and infection. The SARS‐CoV‐2 N501Y.V1 (B.1.1.7) lineage has 17 nonsynonymous mutations and deletions, many of which are in the S protein. The N501Y.V2 (B.1.351) strain contains 10 mutations in the S protein, three of which are in the RBD . The N501Y.V1 and N501Y.V2 lineages exhibit higher transmission efficiency and immune evasion against neutralizing antibodies than the original strain.P681H at the S1/S2 spike cleavage site is thought to increase furin cleavage, potentially affecting viral cell entry.Omic–ACE2 complex and made a significant contribution to the binding energies.Omicron has been described as a highly mutated variant with an “unusual constellation of mutations.”The Omicron VOC is also described by the four‐point mutation in the Spike's N‐terminal domain: A67V, T95I, G142D, and N211I, with respective prevalence of 0.6, 24.8, 40.9, and less than 0.003%. Specifically, the in silico model has linked G142D to a change in the supersite epitope that binds NTD‐neutralizing antibodies.The G446S is another SARS‐CoV‐2 RBD's mutation in the Omicron BA.1 variant, which has an impact on how antigen is processed and presented and increases the antiviral activity of vaccine‐induced T cells. This makes it easier for T cells to recognize new variants.We analyzed other structural genes including E, M, and N substitutions. About E gene, we detected the ET9I substitution in all BA.1, BA.2, and mixed lineages groups, which had more than 98% frequency. M‐A63T, M‐D3G, M‐Q19E, M‐G6S, and M‐A194V were observed in BA.1, BA.2, and mixed lineages for the M gene. M‐G6S was not detected in BA.2 and mixed lineages groups. About N gene mutations, E31del, G204R, P13L, R32del, A119T, R203K, PS33del, PG212S, P365L, and M101L were detected. N‐A119T was not presented in mix lineage group. N‐M101L was not identified in BA.2 and mixed groups.It is important to note that nonstructural proteins of SARS‐CoV‐2 (NSPs) primarily affect the innate immune responses of humans, facilitating immune escape.NSP3 has cleavage operations on nsp, via the pLpro domain, including self‐cleavage of NSP3.The transmembrane proteins nsp3, nsp4, and nsp6 hijack and rearrange the membranes of the host endoplasmic reticulum, subsequently inducing the formation of double membrane vesicles (DMVs).NSP5 is the major protease (Mpro) of the SARS‐CoV‐2. NSP5 likewise separates NLRP12 and TAB1 as well as handling long popular polypeptides. This protein is essential for viral infection.SARS‐CoV‐2 nsp12 besides its RdRp activities in viral replication blocks nuclear translocation of IRF3. Translocation of phosphorylated IRF3 into the nucleus is essential for IFN‐β transcription.There are studies on accessory gene mutations and their impact on virus's cell cycle. Mutation in the Omicron variant's various accessory proteins, including ns3, ns6, ns7a, ns7b, and ns8 have been found.In conclusion, we identified different lineages of SARS‐CoV‐2 Omicron variant  during the sixth wave and compared the substitutions in different SARS‐CoV‐2 genes in the sixth wave to previous five COVID‐19 waves in Iran. The results of this study showed that with the progression of the pandemic, the number of mutations increases significantly, which indicates an adaptive evolution of SARS‐CoV‐2 in humans to increase the transmission of the virus. To address this problem, it will be necessary to continuously monitor and analyze the effects of viral genome mutations to develop vaccines and antivirals that are effective against new SARS‐CoV‐2 variants.Kaveh Sadeghi: Performing tests. Sevrin Zadheidar: Performing tests. Arghavan Zebardast: Writing the manuscript. Ahmad Nejati: Investigation. Marziyeh Faraji: Data collection. Nastaran Ghavami: Data collection. Shirin Kalantari: Data collection. Vahid Salimi: Investigation. Jila Yavarian: Designing the study and editing the manuscript. Adel Abedi: Data analysis. Nazanin Zahra Shafiei Jandaghi: Data curation. Talat Mokhtari‐Azad: Supervision.The authors declare no conflicts of interest.https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/irv.13135.The peer review history for this article is available at


Changes in biodiversity often affect ecosystem functioning. However, most previous biodiversity and ecosystem functioning (BEF) studies have generally been limited to very small spatial grains. Thus, knowledge regarding the biodiversity–ecosystem functioning relationships across spatial scales is lacking. Moreover, the multiscale nature of biodiversity, and specifically β diversity  was still largely missing in BEF studies. Here, using the vegetation and functional trait data collected from four 6‐ha forest dynamics plots (FDPs) in temperate and tropical forests in China, we examine the scale‐dependent relationships between tree diversity and the aboveground biomass (AGB), as well as the roles of species spatial heterogeneity in determining the AGB. In tropical forests, the effect of species richness on AGB decreased with spatial grains, while functional dominance played a stronger role at larger spatial grains. In temperate forests, positive relationship between diversity and AGB occurred at all spatial grains, especially on smaller scales. In both temperate and tropical forests, β diversity was positively correlated with AGB, but weaker than α diversity in determining AGB. Overall, complementarity and selection hypothesis play dominant role in determining AGB in temperate and tropical forests, respectively. The roles of these underlying mechanisms are more pronounced with increasing spatial scales. β diversity, a hitherto underexplored facet of biodiversity, is likely to increase ecosystem functions by species spatial turnover and should not be neglected in BEF explorations. Our findings have practical implications for forest management and demonstrate that biotic heterogeneity plays an important positive role in ecosystem functioning. Roles of α‐ and β‐diversity in determining AGB were examined. The roles of complementarity and selection are scale‐dependent. β diversity is likely to increase ecosystem functions via species spatial turnover. In each region, two 6‐ha (300 m × 200 m) forest dynamics plots (FDPs) were selected, which we refer to Jianfengling and Bawangling FDPs  in the tropical forest, and Jiaohe and Lushuihe FDPs  in the temperate forest. The JFL FDP, which represents the old‐growth tropical montane rainforest, is located in the Jianfengling National Nature Reserve in the south‐western region of Hainan Island, China . The census methodology was identical for all FDPs: All woody stems with a diameter at breast height (dbh) of 1 cm or larger were spatially mapped, measured, and identified to the species level, and tagged. Each FDP was subdivided into nonoverlapping quadrats at three spatial grains: 20 m × 20 m (0.04 ha), 50 m × 50 m (0.25 ha), and 100 m × 100 m (1 ha), for analyzing the scale‐dependent relationships between diversity and ecosystem function. Only individuals with dbh ≥5 cm were used in calculations of the aboveground biomass (AGB) in this study. For each species, we obtained values of five plant functional traits: specific leaf area , leaf dry‐matter content , leaf nitrogen content , leaf phosphorus content , and wood density . Plant leaf traits are related to a species' resource use efficiency  or “moist” (1500–3500 mm year−1). We then calculated AGB for individual, live trees using allometric equations for dry and moist forests from Chave et al.  and Pielou's evenness (J) for each quadrat at each spatial grain. Functional diversity describes the variability in functions or characteristics of the species in a community. As functional diversity metrics, we calculated the functional richness (FRic), functional evenness (FEve), functional divergence (FDiv)  and its components: turnover (βJTU) and nestedness (βJNE) were calculated using multiple‐site dissimilarity by “betapart” package  and aboveground biomass  in the tropical forest FDPs were significantly higher than those in the temperate forest  ranged from 4 to 65; averagely, 30.9, 40.0, 9.0, and 8.7 in BWL, JFL, JH, and LSH FDP, respectively Figure . On avery Figure . SpeciesThe relationships between aboveground biomass and species diversity, functional diversity, and functional dominance (represented by CWM) varied with forest types and spatial grains Figure . In the Our results indicated that at a very small spatial grain (0.04 ha), species richness was significantly and positively correlated with aboveground biomass in both tropical and temperate forests Figure . At a laR2 = .483; Temperate: R2 = .348). However, the explanatory power of the model (R‐squared) and the standardized regression weight (SRW) coefficients indicated that α diversity is more efficient than β diversity in explaining the variation of aboveground biomass in our FDPs . For instance, the community‐weighted trait means (CWMs) explained more variation in AGB than did species diversity and functional diversity at 0.25 and 1 ha grains in tropical forests. This suggested that the selection effect may play a dominant role in aboveground biomass in tropical forests. Moreover, the larger the spatial scale, the more obvious the leading roles of the selection effect on the aboveground biomass in tropical forests. In temperate forests, however, species richness showed positive correlation with aboveground biomass at any spatial grains, suggesting that the role of species diversity in temperate forests was always important to aboveground biomass. These results indicated that niche complementarity effects might be the dominant mechanism in determining the aboveground biomass in temperate forests. Some studies suggested that niche complementarity is less important in stable and high‐yield environments where interactions between species are dominated by competition rather than complementarity, while the positive effects of niche complementarity on productivity, biomass, or C storage are particularly important in unstable and stressful environments , the spatial scale considered in present study is still on the local scale . Second, we investigated the relationship between β diversity and the individual ecosystem function , rather than the relationship between β diversity and multifunctionality at the landscape level as few previous studies have shown . The multi‐institutional network supported long‐term data collection at 73 forest research sites across the Americas, Africa, Asia, Europe, and Oceania. The unprecedented network may support the potential scientists to explore the relationship between β diversity and aboveground biomass not only at multiple spatial scales, but also the relationship between β diversity and multifunctionality at the scale of the regional even to the continental level. Focusing on this not currently well‐examined dimension of biodiversity  has the profound potential not only to help quantify the importance of biodiversity in maintaining (multiple) functioning but also to mechanistically uncover observed patterns of spatiotemporal variation in species assemblage and ecosystem function.We investigated the relationships between β diversity and aboveground biomass just at the spatial grains of 0.04 ha, considering that the 6‐ha plot is not a large enough area to study the relationship at multiple spatial scales. We thus failed to clarify how do the relationships between β diversity as well as their components  and aboveground biomass vary with spatial scales. In fact, there are two aspects of spatial scale: grain and extent. It is worth to explore the relationship between β diversity and ecosystem (multi‐)functionality: (1) at multiple spatial scales , and (2) at the scale of the regional or continental level . The Forest Global Earth Observatory (ForestGEO), previously known as Center for Tropical Forest Science (CTFS), is a global network of forest research sites and scientists dedicated to the study of tropical and temperate forest function and diversity  in maintaining the ecosystem functioning are the major research gap until now. Our study supported a positive correlation between β diversity and aboveground biomass, albeit at the local spatial scale. Moreover, we found that β diversity was weaker than α diversity in explaining variation in AGB in our forests. However, there is an emerging question, saying, whether α‐ or β‐diversity is the most important driver for ecosystem functioning, and which mechanisms drive BEF relationships at larger spatial scales. Anyway, β diversity should not be neglected in BEF explorations in the context of multifunctionality across large areas of spaces. Our study provides implications that it is important to conserve the biotic heterogeneity especially under the context of increasingly biotic homogenization.Jie Yao: Data curation (lead); formal analysis (lead); investigation ; methodology ; writing – original draft (lead). Jihong Huang: Data curation ; funding acquisition (lead). Runguo Zang: Conceptualization (lead); funding acquisition ; resources (lead); validation (lead); writing – original draft .The authors declare no conflict of interest.Data S1. Supporting Information.Click here for additional data file.