Globally, the epidemiology of non‐SARS‐CoV‐2 respiratory viruses like respiratory syncytial virus (RSV) and influenza virus was remarkably influenced by the implementation of non‐pharmacological interventions (NPIs) during the COVID‐19 pandemic. Our study explored the epidemiological and clinical characteristics of pediatric patients hospitalized with RSV or influenza infection before and during the pandemic after relaxation of NPIs in central China.This hospital‐based prospective case‐series study screened pediatric inpatients (age ≤ 14 years) enrolled with acute respiratory infections (ARI) for RSV or influenza infection from 2018 to 2021. The changes in positivity rates of viral detection, epidemiological, and clinical characteristics were analyzed and compared.Median ages of all eligible ARI patients from 2018–2019 were younger than those from 2020–2021, so were ages of cases infected with RSV or influenza . Where the positivity rate for influenza was considerably decreased in 2020–2021  as compared with 2018–2019 , it was increased for RSV  in the same period. The number of severe cases for both RSV and influenza infection were also decreased in 2020–2021 compared with 2018–2019.The implemented NPIs have had varied impacts on common respiratory viruses. A more effective prevention strategy for RSV infections in childhood is needed. In China, the nationwide implemented non‐pharmaceutical interventions (NPIs) were relaxed in April 2020 when the transmission of COVID‐19 was under control.After implementation of NPIs, a remarkable reduction in the circulation of influenza was commonly observed in almost all temperate zones and some tropical areas of the world.In this study, we aimed to report the impact of COVID‐19 NPIs on the epidemiology and clinical characteristics of RSV and influenza infections in hospitalized pediatric patients from central China. Based on this prospective case‐series study, multiple comparisons were made between these infections before and during the pandemic.22.1This hospital‐based prospective case‐series study took place in Henan Children's Hospital, Zhengzhou. Zhengzhou is the capital city of Henan Province in central China with a permanent resident population of 2.4 million children aged 0–14 years.The study was conducted on the largest campus (East Campus) of Henan Children's Hospital where three‐fourths of all the inpatients were admitted. Participants were enrolled in three wards: general emergency ward, infant ward, and pediatric intensive care unit (PICU) as per the severity of illness. The PICU and general emergency ward admitted children aged 6 months to 14 years old, and infants (28 days to 6 months) were admitted to the infant ward.All inpatients aged 14 years or less were screened for ARI. The inclusion criteria for an ARI patient needed: (i) admission to hospital with new illness onset of suspected ARI within 7 days for patients aged >3 months and an onset within 10 days for infants aged ≤3 months; (ii) manifestation of at least one of respiratory symptoms including cough, sore throat, rhinorrhea, and congestion of the nasal mucosa or pharynx; (iii) development of acute fever with an axillary temperature measured ≥37.5°C for patients aged >3 months. The date of illness onset was defined as the day when the symptom was first noticed.2.2Acute respiratory infection (ARI): A comprising infection caused by infectious pathogens such as bacteria and viruses leading to acute inflammation in any part of respiratory system. It is divided into upper or lower respiratory infection based on anatomy.Severe RSV or influenza illness: Illness requiring respiratory‐support with non‐invasive positive pressure ventilation , or invasive ventilation , ICU admission or event of in‐hospital death.Relaxation of NPIs: A post‐epidemic state in which all provinces eased their public health measures with relaxation of human mobility, reopening of schools and businesses, resumption of recreational activities while maintaining social distancing.Pre‐term birth: Babies are born alive before 37 weeks of pregnancy are completed.2.3The enrolled ARI patients were approached for collection of respiratory specimens (throat swabs) within 24 h of hospitalization and then tested within 48 h for RSV and influenza infection by real time‐polymerase chain reaction (RT‐PCR). Methods for influenza and RSV detection are detailed in 2.4Demographics, medical history, underlying conditions such as pre‐term birth, and clinical information  were extracted from electronic medical records of the hospital. The extracted data were recorded using a standardized data dictionary and REDCap system  or EpiData v3.1. The data were checked for completeness and accuracy by the investigators. Information on birth weight and feeding patterns in the first year of life was also recorded if available.2.5Continuous variables were described with medians and interquartile ranges (IQR) and categorical variables were described with frequencies and percentages. Comparisons of RSV or influenza infection characteristics were made using chi‐square test. In case of limited data availability, Fisher's exact test was used, whereas non‐normal distributed continuous variables were compared using Mann–Whitney–Wilcoxon test. Multivariable logistic regression models were developed to identify the potential factors associated with severe illness, calculation of odds ratios (ORs), and 95% confidence intervals. We first used a univariate regression model for candidate variable selection (P < 0.1), then performed a forward stepwise model selection based on Akaike's information criterion (AIC) and likelihood ratio test to select the explanatory variables in final model. Candidate variables are listed in the 33.1Throughout the study years, a total of 7093 eligible ARI patients were admitted in the three wards. Out of these eligible patients, 5250 (74.0%) patients with an informed consent were enrolled in this study. Remaining 1843 (26.0%) patients were excluded from the study on guardians' request. The main reason behind refusal of participation was the guardians' unwillingness for their children to receive the throat swab sampling procedure. Additional 11 patients were excluded due to incomplete medical records. In the end, 5239 patients remained in study for the screening of influenza and RSV infection. These 5239 patients included 3275 patients from 2018–2019 and 1964 patients from 2020–2021 Figure .Generally, the median age of ARI patients in 2018–2019 was younger than those enrolled in 2020–2021   cases were found to be caused by RSV or influenza. These included 372 (11.4%) cases of RSV, 94 (2.9%) cases of influenza, and 19 (0.6%) cases of co‐infection. Since our focus was on the single viral pathogen infected patients, the data from 19 cases of co‐infection were excluded. The remaining 2790 (85.2%) cases were negative for RSV as well as influenza. In the second study year 2020–2021, there were 289 (14.7%) cases of RSV or influenza infection. These included 262 (13.3%) cases of RSV and 27 (1.4%) cases of influenza. No cases of co‐infection were detected in this study year  as well as influenza  . The most common underlying conditions included pre‐term birth (8.9% [33/372] in 2018–2019 and 6.5% [17/262] in 2020–2021) and congenital heart disease (CHD) (2.4% [9/372] in 2018–2019 and 0.8% [2/262] in 2020–2021). A similar decreasing trend of underlying conditions was observed in influenza‐infected patients (2018–2019: 13.8% [13/94] vs. 2020–2021: 7.4% [2/27]) Table .3.4As shown in Table The main treatment options for RSV infection relied on supportive care. The proportion of patients receiving any forms of oxygen treatment in 2018–2019 (26.6%) was more than those from 2020–2021 . The influenza‐infected patients received the well‐established antiviral treatment of neuraminidase inhibitors, and its proportion was higher in 2018–2019 than 2020–2021 (P < 0.05). Antibiotic treatment was often prescribed in both viral infections and their proportions did not differ during the pandemic. Overall, 96.2% (610/634) of RSV and 95.0% (115/121) influenza‐infected patients received antibiotics. 34.9% (221/634) RSV‐infected patients and 17.4% (21/121) influenza‐infected patients were treated with corticosteroids (P < 0.05) (Table 7.5% (28/372) cases of RSV‐infected patients were identified as severe cases in 2018–2019 which dropped to 1.9% (5/262) in 2020–2021. The frequency of non‐invasive positive pressure or requirement of invasive ventilation was higher in 2018–2019 (4.8%) than in 2020–2021 (1.1%) (P < 0.05). Similar pattern was observed for the number of ICU admissions . The number of severe influenza cases decreased from 16.0% (15/94) in 2018–2019 to none in 2020–2021. Similarly, the number of ICU admissions significantly dropped from 16.0% (15/94) in 2018–2019 to 0% (0/27) in 2020–2021. In univariate and multivariate analyses, we found the children with CHD and living outside Zhengzhou were more likely to be associated with severe outcomes Tables  and S7.4Our study reported a significantly reduced influenza activity in 2020–2021 which was similar to the studies from the United States and the United Kingdom.As compared to 2018–2019, a higher median age was observed in 2020–2021 in patients of ARI, RSV, and influenza Table .Meanwhile, the proportion of severe RSV or influenza illness was lower in 2020–2021 than 2018–2019. This finding was similar to the studies from Latin America, France, and Shanghai,Several limitations to our study should be noted. First, we might have underestimated the influenza infection. For prevention of nosocomial infections, rapid antigen tests for influenza   were constantly conducted in all outpatient departments of Henan Children's Hospital for patients with influenza‐like illness (ILI) Table . For the5The NPIs during COVID‐19 pandemic had varied impacts on common respiratory viruses. This was associated with a remarkably reduced incidence of influenza, while RSV infections remained at a higher level. This observation highlighted the need to find a most effective preventive strategy for RSV infections in childhood.Lingshuang Ren: Conceptualization; data curation; formal analysis; investigation; writing – original draft. Li Lin: Data curation; project administration. Hua Zhang: Data curation; project administration. Qianli Wang: Conceptualization; project administration; investigation; writing – original draft. Yibing Cheng: Project administration. Qin Liu: Project administration. Bing Fang: Investigation. Linsen Xie: Project administration. Meng Wang: Investigation. Juan Yang: Writing – review and editing. Jinxin Guo: Formal analysis. Tianchen Zhang: Investigation. Hongkai Lian: Supervision. Jiangtao Wang: Supervision. Hongjie Yu: Conceptualization; supervision; writing – review and editing.HY has received research funding from Sanofi and Shanghai Roche Pharmaceutical Company. All other authors declare no competing interests.The study was approved by School of Public Health, Fudan University (IRB No. 2018‐06‐0686 and IRB No. 2020‐12‐0864) and Research Ethics Commission of Henan Children's Hospital.For patients under 7 years, informed consent forms were signed by their legal guardians. Patients aged between 7 and 11 years signed simplified forms, and their guardians signed the full versions. Patients older than 12 years and their guardians signed the full version forms.https://publons.com/publon/10.1111/irv.13103.The peer review history for this article is available at Table S1. Demographic characteristics among all eligible, enrolled and excluded ARI patientsTable S2. Positive rate of RSV and influenza in enrolled ARI inpatientsTable S3. Detailed underlying conditions of patients before admissionTable S4. Clinical presentations of patients with RSV and influenza infection at admissionTable S5. Laboratory findings of patients infected with RSV and influenza infection at admissionTable S6. Univariate analysis of risk factors associated with ICU admission, mechanical ventilation or in‐hospital deathTable S7. Multivariate analyses of risk factors associated with ICU admission, mechanical ventilation or in‐hospital deathTable S8. Influenza rapid test of ILI outpatientsClick here for additional data file.


Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses.In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non‐diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies.A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses.We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology. Sporadic inclusion body myositis (sIBM) is the most common inflammatory myopathy in the elderly,VCP, have been identified,The pathogenesis of sIBM is thought to have two mechanisms: inflammation and degeneration. Inflammatory mechanisms are supported by infiltration of CD8‐positive cells in histopathology and anti‐cytosolic 5′‐nucleotidase 1A (cN1A) autoantibodies in the sera of a certain population of sIBM patients.Metabolomics is a method for identifying changes in metabolic pathways by identifying small molecules in a biological system, but few studies have explored the metabolomics of muscular diseases. A study of the metabolomic analysis of various myopathies revealed alterations in several metabolic pathways, including transsulfuration, creatine, and niacinamide, in the blood of sIBM patients,The present study aimed to elucidate the metabolic profiles of sIBM via metabolomic and transcriptomic analyses of biopsied muscle specimens of sIBM patients and identify novel therapeutic targets of this devastating age‐related myopathy.To identify the metabolic profile of sIBM muscle, we analyzed muscle samples biopsied from 14 sIBM patients (10 men and four women) and age‐ and sex‐matched six healthy subjects. In an attempt to perform RNA sequencing, we also analyzed muscle samples biopsied from 12 sIBM patients (eight men and four women) and age‐ and sex‐matched five non‐diseased subjects. Of those, seven sIBM and five non‐diseased subjects underwent both metabolomic and transcriptomic analyses. All sIBM patients were diagnosed as clinicopathological defined IBM according to the European Neuromuscular Centre IBM research diagnostic criteria 2011.We performed an open muscle biopsy for diagnostic purposes, as previously described.g and 4°C for 5 min. Subsequently, 400 μL of the upper aqueous layer was centrifugally filtered through a Millipore 5 kDa cutoff filter at 9100g and 4°C for 120 min to remove proteins. The filtrate was centrifugally concentrated and resuspended in 50 μL of Milli‐Q water for CE‐TOFMS analysis.Metabolite extraction was conducted at Human Metabolome Technologies (HMT), Japan. For capillary electrophoresis time of flight mass spectrometry (CE‐TOFMS) analysis, approximately 30 mg of frozen muscle tissue was plunged into 750 μL of 50% acetonitrile/Milli‐Q water containing internal standards  at 0°C to deactivate enzymes. Tissues were homogenized 10 times at 3500 rpm for 60 sec using a tissue homogenizer, and then, the homogenate was centrifuged at 2300m/z 50 to 1000. Other conditions were performed as described previously.Metabolome measurements were performed through a facility service at HMT. CE‐TOFMS was performed using an Agilent CE Capillary Electrophoresis System equipped with an Agilent 6210 Time of Flight mass spectrometer, Agilent 1100 isocratic HPLC pump, Agilent G1603A CE‐MS adapter kit, and Agilent G1607A CE‐ESI‐MS sprayer kit . The systems were controlled by Agilent G2201AA ChemStation software version B.03.01 for CE . Metabolites were analyzed using a fused silica capillary , with commercial electrophoresis buffer  as the electrolyte. Samples were injected at a pressure of 50 mbar for 10 sec (approximately 10 nL) for cation analysis and 25 sec (approximately 25 nL) for anion analysis. The spectrometer was scanned from m/z, migration time for CE‐TOFMS measurement (MT), and peak area.m/z values determined via TOFMS. The tolerance range for peak annotation was configured at ±0.5 min for MT and ±10 ppm for m/z. Furthermore, peak areas were normalized against internal standards; then, resultant relative area values were further normalized according to sample amount. Multiple possible metabolites were noted if several annotations were assigned to a single peak.Peaks were extracted using automatic integration software MasterHands  to obtain peak information, including We extracted RNA from frozen biopsied muscle tissues of 12 sIBM patients and five non‐diseased subjects using the miRNeasy Mini Kit (Qiagen). Total RNA was quantified using a 2100 Bioanalyzer with an RNA 6000 Pico Kit (Agilent Technologies). Libraries were prepared using the Illumina TruSeq Stranded Total RNA Library Prep according to the manufacturer's protocol (Illumina) and then sequenced with Illumina HiSeq 2500 (PE‐150 nt).https://www.bioinformatics.babraham.ac.uk/projects/trim_galore/). The quality of sequence reads was assessed using FastQC v. 0.11.8 (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/) before and after trimming. Processed reads were mapped on human genome version hg19 using HISAT2 v. 2.1.0Adapter sequence trimming and low‐quality  base removal were processed with Trim Galore v. 0.5.0 .To determine mast cells, sections of muscle samples were fixed and stained with toluidine blue according to a previously reported procedure.Immunohistochemical studies were performed as previously described.https://www.reactome.org/) on the 20 metabolites with high VIP scores. RNA‐seq data were assessed using Prism 8 (GraphPad Software). Values were presented as mean ± standard deviation. Student's t‐test or Welch's t‐test was used for comparing two groups.Targeted metabolomics data were analyzed using MetaboAnalyst 3.0.m/z values and migration time, a total of 198 metabolites were identified in CE‐TOFMS analysis. PLS‐DA showed that non‐diseased subjects and sIBM groups were clearly separated , increased more in sIBM skeletal muscle than in non‐diseased subjects Fig. . In suppcle Fig. . The mRNcle Fig. . Collectcle Fig. . To valicle Fig.  and sIBMcle Fig. , their nHYAL1, HYAL2, and HYAL4, genes associated with chondroitin sulfate degradation were downregulated , SLC25A20 (carnitine‐acylcarnitine carrier), and SLC6A8 (creatine transporter) were lower in sIBM skeletal muscle than non‐diseased subjects Within the nucleotide sugar metabolism pathway, we revealed enhanced biosynthesis of some nucleotide sugars, which are components of glycosaminoglycans. We also demonstrated insufficient degradation of chondroitin sulfate in metabolomic and transcriptomic analyses, as well as its deposition in the interstitium of sIBM muscle specimens from histopathological studies. By contrast, neither heparan sulfate nor the keratan sulfate pathways were affected in histopathology. These pathological and transcriptomic findings suggest that excessive chondroitin sulfate is involved in sIBM pathophysiology. Chondroitin sulfate proteoglycan 4 plays a role in both fibrogenic differentiation induced by transforming growth factor‐β (TGF‐β) and adipogenic differentiation from basic fibroblast growth factor in skeletal muscle.We also found carnitine and creatine deficiency in sIBM skeletal muscle. Both carnitine and creatine play important roles in energy metabolism. Carnitine deficiency in skeletal muscle has been described in various myopathiesThe present study has several limitations. First, this was an exploratory study with a limited sample size. Second, since participants did not fast before the biopsy, the effect of metabolic changes due to dietary content cannot be excluded. Furthermore, only Japanese subjects were included in the study, although the effects of ethnicity on sIBM have not been clarified.In summary, our results indicate that metabolic pathways for histamine, chondroitin sulfate, creatine, and carnitine are altered in the skeletal muscle of sIBM patients and are potential therapeutic targets for this devastating myopathy for which no effective treatment has been available.Nothing to report.A.M., S.N., and M.K. contributed to the conception and design of the study; A.M., S.N., T.K., S.H., S.Ki., H.N., K.M., K.T., M.I., H.K., K.S., and Y.H. contributed to the acquisition and analysis of the data; A.M. and S.N. contributed to drafting the text and preparing the figure; and S.Ku., K.K., T.S., T.O., and M.K. revised the manuscript critically for important intellectual content.


Metabolic syndrome (MetS), a group of risk factors that define metabolic dysfunction in adults, is strongly associated with obesity and is an emerging risk factor for cancer. However, the association of MetS and degree of metabolic dysfunction with obesity‐related cancer is unknown.Using National Health and Nutrition Examination Survey data from 1999 to 2018, we identified 528 obesity‐related cancer cases and 18,972 cancer‐free participants. MetS was defined as the presence of or treatment for ≥3 of hyperglycemia, hypertension, hypertriglyceridemia, low HDL–cholesterol, and abdominal obesity. A metabolic syndrome score (MSS) was computed as the total number of abnormal MetS parameters to determine the severity of metabolic dysfunction. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models, adjusting for sociodemographic and lifestyle factors.About 45.7% of obesity‐related cancer cases were classified as having MetS compared with only 33.0% of cancer‐free participants. Overall, MetS and MSS were not associated with obesity‐related cancer. However, MSS was associated with higher obesity‐related cancer risk among participants under 50 years of age (OR [95% CI] = 1.28 [1.08–1.52]). When evaluating MSS categorically, compared with healthy participants with no abnormal MetS parameters (MSS = 0), participants with one or two abnormal parameters had a statistically significant higher risk of obesity‐related cancer (OR [95% CI] = 1.73 [1.06–2.83]).Metabolic dysfunction is associated with a higher risk of obesity‐related cancer, particularly in young adults under 50 years of age, and among participants with one or two abnormal metabolic parameters. A more accurate indicator of metabolic dysfunction, beyond metabolic syndrome, is needed to better assist in stratifying individuals for obesity‐related cancer risk. Participants with mild metabolic dysfunction i.e., 1‐2 abnormal metabolic syndrome (MetS) parameters, especially participants younger than 50 years, have a higher risk of obesity‐related cancer (ORC) compared to participants with zero abnormal MetS parameters. Traditionally, these individuals would not have been clinically diagnosed with MetS or perceived to be at higher risk for ORC, suggesting that measures beyond the clinical MetS diagnosis need to be considered to stratify individuals with respect to their ORC risk. We also excluded participants with a cancer diagnosis other than obesity‐related cancer , fasting hypoglycemia , and pregnant or lactating women . Additionally, despite being obesity related, we had to exclude all esophageal, gastric, blood, and brain cancers as NHANES lacks the histological and molecular classification needed to determine which ones are obesity related (N = 107 [0.11%]). After all exclusions, the analytical data set included data on 19,500 study participants.All participants in the NHANES database 18 years of age or older that provided a fasting blood sample were eligible to be included in the current analysis. As the MetS definition is based on the presence of three or more abnormal parameters, we excluded participants with three or more missing values for the MetS criteria  criteriaPrevalent MetS was identified using questionnaire information, anthropometric data, and laboratory values. Hyperglycemia was determined by FBG concentration, drug treatment of hyperglycemia, or self‐report of a prior history of diabetes. The presence of hypertension was calculated by an average of at least two SBP or DBP readings, drug treatment for hypertension, or self‐report of a prior history of hypertension. In concordance with previous studies, participants with only one available blood pressure reading were not labeled as having hypertension due to the potential for inaccuracy.The metabolic syndrome score (MSS), calculated as the total number of abnormal MetS components, was computed to determine if the number of abnormal MetS criteria present was associated with obesity‐related cancer risk, beyond the presence of MetS itself. This provides a score rather than a binary measure of metabolic dysfunction, allowing us to evaluate incremental associations of metabolic dysfunction with obesity‐related cancer. The MSS ranged from a minimum possible value of 0  to a maximum of 5 .2.4Participants were classified as having obesity‐related cancer using the NHANES medical condition questionnaires. Obesity‐related cancer sites were determined as defined by the National Cancer Institute (NCI)2.5r2 = 0.90, p < 0.0001), we did not adjust for BMI in the current analysis.Analyses were adjusted for age , sex, race/ethnicity , education level , annual household income , smoking status , alcohol use (yes/no), sedentary behavior , weekly physical activity level , daily calorie intake, and survey year. As WC was statistically significantly correlated with BMI  were changed to missing. Missing covariate values were analyzed as a separate category. In sensitivity analyses, we evaluated the risk of obesity‐related cancer with MetS in a complete case analysis, excluding all participants with missing MetS parameter data. All statistical analyses were carried out using SAS Studio, and significance was determined at α = 0.05.Descriptive statistics and correlations between all MetS components were computed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for obesity‐related cancer risk and association with the various parameters of metabolic health , the presence of MetS, and severity of MetS were estimated using multivariable logistic regression models adjusting for (1) age and sex and (2) age, sex, race/ethnicity, education level, annual household income, smoking status, alcohol use, daily hours sedentary, weekly physical activity, daily calorie intake, and survey year. To determine the degree to which the associations between MetS, MSS, and obesity‐related cancer were modified by age, sex, race/ethnicity, and BMI, subgroup analyses were conducted using multivariable‐adjusted logistic regression models. Because of the complex survey design of NHANES, all estimates were weighted according to the NHANES analytic guidelines to be representative of the U.S. civilian noninstitutionalized‐resident population.3In the current analyses, we evaluated associations of MetS and other metabolic dysfunction parameters with obesity‐related cancer among NHANES participants from 1999 to 2018. Baseline characteristics with weighted proportions are summarized in Table Table r = 0.84).Mutual correlations between the various metabolic dysfunction parameters are outlined in Table Neither the presence of MetS nor the severity of MetS as indicated by increasing MSS was associated with obesity‐related cancer overall  Table . In subgAdditional subgroup analyses were conducted to evaluate differences by age, sex, race/ethnicity, and BMI Figure . There w2) were older; 59.1% of cancer‐free overweight participants were under 50 years of age compared with 69.2% of normal weight cancer‐free participants. As expected, all metabolic parameter levels were worse for overweight cancer‐free participants compared with normal weight cancer‐free participants. Obesity‐related cancer participants were more likely to be older and female compared with overweight cancer‐free participants, owing to the association of age with cancer development and most obesity‐related cancers being cancers of the female reproductive system. Notably, metabolic parameters were very similar between obesity‐related cancer cases and overweight cancer‐free participants. Metabolic parameters were mostly worse for obesity‐related cancer cases, except, however, for HOMA‐IR and abdominal obesity, adding to the hypothesis that metabolic dysfunction may be an important component of cancer risk.We performed an additional analysis comparing normal weight and overweight cancer‐free participants to participants with obesity‐related cancer Table . In geneBecause many obesity‐related cancers are reproductive cancers, sensitivity analyses were performed by restricting our data set to females and additionally adjusting for menopausal status and HRT use. We also performed a sensitivity analysis for overall obesity‐related cancer risk and breast cancer risk with MetS and MSS, restricting to postmenopausal breast cancer cases only . No significant differences were observed in these analyses compared with the entire population Tables  and S6. 4We examined the association between metabolic dysfunction and obesity‐related cancer in a nationally representative cohort comprised of 528 obesity‐related cancer cases and 18,972 cancer‐free participants. We observed a greater degree of metabolic dysfunction among those that reported obesity‐related cancer compared with cancer‐free participants. For example, almost half of obesity‐related cancer cases had MetS versus just over a third of cancer‐free individuals. Moreover, 93% of obesity‐related cancer cases had at least one abnormal MetS parameter compared with 79% of cancer‐free participants. Our results suggest that metabolic dysfunction even in a single MetS parameter, in contrast to the binary definition of MetS, was positively associated with the presence of obesity‐related cancer.Proposed mechanisms to explain the relationship between MetS and obesity‐related cancer include alterations in hormone signaling, oxidative stress, and chronic low‐grade inflammation.Each of the MetS parameters is associated with cancer development.Radišauskas et al. reported that although there are multiple studies linking total cholesterol levels to increased cancer risk,Dyslipidemia is also an independent risk factor for obesity‐related cancer. Although the MetS parameters may have independent associations with obesity‐related cancer, it remains unclear whether these effects are additive and whether increasing severity of metabolic dysfunction increases cancer risk in a dose–response manner. Our study did not observe that the number of abnormal MetS parameters, calculated as MSS, was monotonically associated with obesity‐related cancer. However, compared with healthy participants , having one or two abnormal MetS criteria was statistically significantly associated with obesity‐related cancer. Traditionally, these individuals (~46%) would not have been clinically diagnosed with MetS. This suggests that mild metabolic dysfunction may increase cancer risk, and measures beyond the clinical MetS diagnosis need to be considered to stratify individuals with respect to their obesity‐related cancer risk.Having MetS was not associated with obesity‐related cancer in this study. However, with evidence that MetS increases cancer‐related mortality,We observed that metabolic dysfunction was associated with obesity‐related cancer among younger adults (<50 years). Recent reports show an increasing incidence of obesity‐related cancer in adolescents and young adults, specifically for colorectal, breast, kidney, uterine, pancreatic, and thyroid cancers.Our study has some limitations. Cancers were self‐reported and, therefore, there is a possibility of misclassification and recall bias. There may also be misclassification of the exposure resulting from imperfect biomarker measurement. However, we anticipate any such misclassification to be non‐differential and, therefore, will only bias the ORs towards the null. Another major limitation is the cross‐sectional nature of the data, thus precluding us from making inferences on temporality. Because of this, we are unable to preclude the temporality of obesity and cancer diagnoses in NHANES participants. Moreover, NHANES does not include data on cancer treatment. It is possible that cancer patients in this population experienced weight reduction after a cancer diagnosis, which could result in the absence of MetS and reverse causality in this study. Multiple mechanisms may be involved in such a weight loss, including reduced food intake, response to cancer treatment, and hypercatabolism resulting from inflammation, tumor metabolism, or insulin resistance.In conclusion, metabolic dysfunction is associated with higher obesity‐related cancer risk, particularly in young adults under 50 years of age and in participants with one or two abnormal metabolic parameters. Previous studies that have only considered those with MetS  as metabolically unhealthy may, in fact, be excluding many metabolically unhealthy individuals at a higher risk for obesity‐related cancer. Further research on metabolic dysfunction could provide insight into potential mechanisms between metabolic parameters and obesity‐related cancer and allow for better risk stratification and cancer prevention strategies in higher‐risk subgroups.Conceptualization: M.W., M.P., and S.H.; methodology: M.W., M.P., and S.H; formal analysis: M.W., M.P., S.H., and B.H.; writing—original draft preparation: M.W. and S.H.; writing—review and editing: M.W., P.K., J.D., S.S., B.H., M.L., M.G., M.P., and S.H; visualization: M.W., M.P., and S.H.; supervision: M.P. and S.H.S.A. Summers is a co‐founder and consultant with Centaurus Therapeutics. All other co‐authors do not declare any conflict of interest.NHANES is a publicly available data set approved by the National Center for Health Statistics institutional review board, and all participants provided written informed consent.Figure S1Click here for additional data file.Table S1‐S7Click here for additional data file.


To analyze the use of packed red blood cells (PRBCs) for patients with pelvic fracture and evaluate factors associated with PRBC transfusion for patients with pelvic fracture.This retrospective cohort study collected 551 patients with pelvic fractures from six hospitals between September 1, 2012, and June 31, 2019. The age span of patients varied from 10 to 95 years old, and they were classified into two groups based on high‐energy pelvic fractures (HE‐PFs) or low‐energy pelvic fractures (LE‐PFs). The study's outcome was the use of PRBCs, fresh frozen plasma (FFP), and albumin. Demographic data, characteristics, laboratory tests, clinical treatment details, and clinical outcomes were compared between the two groups. Factors that were statistically associated with perioperative PRBCs in univariate analyses were included to conduct an optimal scale regression to determine the independent factors for perioperative PRBCs.P < 0.001). There were higher proportions of male patients and patients under 65 in the HE‐PF group . HE‐PF group patients were more severely injured and likely to take external fixation. The optimal scale regression revealed four significant factors associated with perioperative transfused PRBCs, which were patients on admission with hemorrhagic shock , followed by fracture types identified by Tile classification , hemoglobin levels below 70 g/L on admission , followed by fracture types identified by Tile classification , hemoglobin levels below 70 g/L on admission , and methods of pelvic fixation , ranked by the importance.A total of 551 patients were screened from six hospitals, and after inclusion and exclusion, 319 were finally included and finished the follow‐up from admission to discharge, while four patients died during hospitalization. Three hundred and nineteen patients were classified into two groups by their injury mechanisms. A total of 230/319 (72.1%) patients were classified into the HE‐PF group, and 89/319 (27.8%) patients were classified into the LE‐PF group. Patients in the HE‐PF group were transfused with 4.5 (3–8) units of PRBCs, 300 (0–600) ml of FFP, and 0 (0–30) g of albumin, while patients in the LE‐PF group were transfused with 3.5 (2–4.5) units of PRBCs, 0 (0–295) ml of FFP, and 0 (0–0) g of albumin . High‐energy pelvic fractures (HE‐PFs) are commonly seen in traffic accidents and falls from heights,Patients with HE‐PFs require a multidisciplinary team approach to address their complex life‐threatening lesions, and the Damage Control Orthopedics protocol is mainly applied.Although necessary for orthopedic patients' treatment, the transfusion of allogeneic red blood cells is controversial. In addition to a safe blood supply, people are aware of the unwanted increased mortality and complications related to blood transfusion for patients undergoing surgeries.Based on previous studies, the severity of pelvic ring disruption was positively correlated with the overall red blood cell transfusion for orthopedic patients; open book fractures, whether based on fracture classifications of Tile classification or Young–Burgess classification, were associated with more transfusion requirements.Most studies have implied possible factors that could increase the tendency of PRBC transfusion, but they mainly focused on one element of transfusion or the use of PRBCs during a specific period of inpatient time. Since the transfusion of PRBCs’ results from a multitude of factors and the overall transfusion of PRBCs during hospitalization has never been evaluated, our study was designed to: (i) evaluate the perioperative transfusion of PRBCs; and (ii) identify independent predictors for the perioperative transfusion of PRBCs, and help to draw attention to such patients with more effective implementation of PBM on them.The inclusion criteria were as follows: (i) patients who received internal fixation (IF), external fixation (EF), or conservative treatment for pelvic stabilization; and (ii) patients who were admitted with diagnoses of pelvic fractures.The exclusion criteria were as follows: (i) patients who did not receive any transfusion of PRBCs; (ii) patients who had suffered from pelvic fractures 3 months before admission; (iii) patients who had preexisting blood coagulation disorders; and (iv) patients who were transferred from or to another hospital, or abandoned treatment in the course of treatment.We collected data on the demographics, characteristics, laboratory tests, therapeutic courses, and clinical outcomes of 551 patients from electronic patient systems of six different hospitals between September 1, 2012, and June 31, 2019. HE‐PFs were high‐energy caused injuries, including traffic accidents, falls from height, and industrial and agricultural injuries, while LE‐PFs were low‐energy caused injuries, including falls to the ground and low‐energy external forces.All procedures were performed under general anesthesia with the patient in a supine or lateral position as needed.A 5 cm long incision was made at the anterior superior iliac spine to expose the iliac fracture. Another 15 cm long incision was made along the hip to expose the pelvic fracture end and the posterior wall of the acetabulum through the posterior iliac wing. The reduction was held by pelvic reduction forceps (Orthofix). The steel plate (Orthofix) was fixed to the fracture end of the pelvis and the posterior wall of the acetabulum with an appropriate curvature. The depth of the steel plate was measured after drilling, and proper length screws  were placed above and below to fix the plate and ilium  of the external fixator were inserted; after checking the position under the C arm (SSME), the connecting rod (Orthofix) was installed Figure .Patients received routine orthopedic care, anti‐infection, fluid replacement, and other symptomatic supportive treatment, and they were immobilized in bed, intensively observed, and nursed.Conservative treatment was administered to patients who did not need surgical treatment, refused surgical treatment, or had contraindications for surgeries. One patient only underwent one pelvic radiograph on the first day after admission, and this radiograph showed a stable pelvic fracture with no indication for surgery Figure .9/L was selected as a threshold. The cutoff points of activated partial thromboplastin time (APTT) and prothrombin time (PT) were set to 56 s and 21 s, respectively, 1.5 times those of normal controls. The pelvis Abbreviated Injury Scale represented the severity of pelvic fractures. Types of fractures were identified with Tile classification by a senior orthopedic surgeon based on patient records and radiographs. The American Society of Anesthesiologists (ASA) score was used to classify surgery risk and records of ASA scores were available from patients' anesthesia notes.Routine blood and conventional coagulation tests on admission were performed to determine the patients' blood flow state and coagulation function. The threshold of 70 g/L was chosen to differentiate hemoglobin (Hb) levels; the cutoff point of hematocrit (Hct) levels was chosen as 30%; the platelet count (PC) of 100 × 10Details about the administration of hemostatic drugs, iron supplement agents, the application of autologous blood transfusions, and perioperative transfusions of blood products about PRBCs, FFP, platelets, cryoprecipitate, and albumin were analyzed.The occurrence of adverse transfusion reactions, including hemolytic transfusion reaction (HTR), allergic transfusion reaction (ATR), and transfusion‐related acute lung injury (TRALI), were recorded. Major complications in orthopedic patients, including deep venous thrombosis (DVT) and pressure ulcers, were recorded too. The Matta radiological grading was used to evaluate the pelvic reduction quality based on the measurement on radiographs of anteroposterior (AP), 40° caudad (inlet), and 40° cephalad (outlet) or Judet views.χ2‐test. In univariate analyses of factors associated with perioperative PRBCs, factors with statistical significance and clinical meaning were included to generate an optimal scale model to identify factors associated with the increased perioperative transfusion. A p value <0.05 indicated statistical significance.All parameters were imported into SPSS® Statistics 25.0  and analyzed. All descriptive statistics were classified as continuous and categorical variables; continuous variables were tested by the Shapiro–Wilk test to identify their normal distribution. If they were normally distributed, they are presented as the mean ± standard deviation, but if they were not, they are presented as the median with lower and upper interquartile range; categorical variables in the independent variables are presented as numbers (%) or the median with lower and upper interquartile range. The Kruskal—Wallis test or Mann–Whitney U test was used to evaluate differences in nonnormal distributed continuous variables, while differences in categorical variables were assessed by the A total of 319 patients finished follow‐up of 21 (16–27) days from admission to discharge, and 230 patients were classified into the HE‐PF group, while 89 patients were classified into the LE‐PF group Figure .P < 0.001). The proportion of patients who were younger than 65 years old was higher in the HE‐PF group  than in the LE‐PF group  (P < 0.001). The ratios of patients with angiocardiopathy, diabetes, osteoporosis, and other coexisting diseases were higher in the LE‐PF group than in the HE‐PF group . The ratios of patients with accompanying extremity bone fractures and acetabulum fractures were larger in the HE‐PF group than in the LE‐PF group . The proportions of patients with associated head injuries, nerve injuries, abdominal injuries, genitourinary injuries, hemorrhagic shock, and other injuries were higher in the HE‐PF group   than in the LE‐PF group  (P < 0.001). The ratio of patients discharged with fair pelvic reduction quality was 23.5% (54/230) in the HF‐PF group, which was higher than 12.4% (11/89) in the LE‐PF group (P = 0.027). The ratio of patients discharged with poor pelvic reduction quality was 12.2% (28/230) in the HE‐PF group, which was also higher than 3.4% (3/89) in the HE‐PF group (P = 0.017). In the HE‐PF group, two patients died of severe injuries 1 week after admission and one patient died 10 days after admission due to an infection related to an open fracture. One patient in the LE‐PF group with a craniocerebral injury caused by a fall onto the ground died 16 days after admission. The median length of hospital stay was prolonged in the HE‐PF group by 22 (17–29) days, compared with 18 (13–22) days in the LE‐PF group (P < 0.001)  in the LE‐PF group and 18.7% 43/230) in the HE‐PF group, with no difference found in the two groups. The percentage of patients discharged with good pelvic reduction quality was 74.2% (66/89) in the LE‐PF group, which was higher than 45.7% (105/230) in the HE‐PF group (30 in theP = 0.002), and the ratio of patients diagnosed with Tile A2 fracture was 55.1% (49/89) in the LE‐PF group, larger than 27.4% (63/230) in the HE‐PF group (P < 0.001). There was a higher proportion of patients diagnosed with Tile B1 fractures in the HE‐PF group  than in the LE‐PF group  (P = 0.033), and there were larger proportions of patients diagnosed with Tile C1 and C2 fractures in the HE‐PF group than in the LE‐PF group  (Table The ratio of patients diagnosed with Tile A1 fracture was 18% (16/89) in the LE‐PF group, larger than 6.5% 15/230) in the HE‐PF group (0 in the P = 0.031). Patients with Hct levels below 30% were 180/319 (56.4%) in total and 142/230 (61.7%) patients were in the HE‐PF group, while 38/89 (42.7%) patients were in the LE‐PF group (P = 0.002) (Table The results of blood tests on admission showed that 47/319 (20.1%) patients were found to have Hb levels below 70 g/L, 40/230 (21.3%) of whom were in the HE‐PF group and 7/89 (16.9%) of whom were in the LE‐PF group (P = 0.013). More patients in the HE‐PF group chose IF as pelvic stabilization, while more patients in the LE‐PF group chose EF as pelvic stabilization . No differences were found in other elective surgeries performed for patients between the two groups , and ratio of patients administered iron supplement agents was also higher in the HE‐PF group  than in the LE‐PF group  (P < 0.001). PRBCs, FFP, and albumin were more frequently transfused in the HE‐PF group ; patients in the HE‐PF group were transfused with 4.5 (3–8) units of PRBCs, 300 (0–600) ml of FFP, and 0 (0–30) g of albumin, while patients in the LE‐PF group were transfused with 3.5 (2–4.5) units of PRBCs, 0 (0–295) ml of FFP, and 0 (0–0) g of albumin  than in the LE‐PF group  , and male patients were transfused with more PRBCs than female patients (P = 0.001). Moreover, patients with comorbidities of angiocardiopathy, diabetes, or osteoporosis were transfused with fewer PRBCs than those without such comorbidities, respectively .On analyses of factors that were statistically associated with perioperative PRBCs, patients aged <65 years were transfused with more PRBCs than patients ≥65 years (Ps < 0.01). Patients identified with Tile A1 to C3, were transfused with 4 (2.5–5.5), 3.8 (2–5.5), 7 (1.8–8.5), 4 (3–5.5), 4 (3–8), 4.3 (2.8–8.3), 5.5 (3–11), 6 (3.3–9), and 8.5 (6–10.5) units of PRBCs, respectively (P = 0.001). Further analyses of differences between groups showed that there were differences in transfused PRBCs between patients with Tile A2 and C3 , patients with Tile A1 and C3 , and patients with Tile B1 and C3 .Patients with associated abdominal injuries, genitourinary injuries, or hemorrhagic shock were transfused with more PRBCs than those without such associated injuries, respectively . Patients who underwent emergency surgeries of exploratory laparotomy, angiographic embolization, or ruptured organ resection received more PRBCs than those who did not undergo such emergency surgeries, respectively . Methods of pelvic stabilization were associated with different PRBCs; patients who had IF fixation were transfused with 4 (3–7.9) units of PRBCs, patients who had EF fixation with 3.5 (2–5.6) units of PRBCs, and patients who received conservative treatment with 4 (2–6.5) units of PRBCs (P = 0.045). Further analysis identified a difference of PRBC transfusion between IF and EF fixation . Patients who underwent extremity fracture fixation surgeries received more PRBCs than those who did not (P = 0.005). Patients administered hemostatic drugs received more PRBCs than those who were not (P < 0.001) , ensuring that there were statistically significant relations between the included variables and perioperative PRBCs. The correlation and tolerance examination excluded collinear relationships between the independent variables because the tolerance of each variable after conversion was above 0.6. Independent variables with statistical significance were the presence of hemorrhagic shock on admission , pelvic fractures identified by Tile classification , hemoglobin levels below 70 g/L on admission , and methods of pelvic fracture fixation   patients in the HE‐PF group who suffered from delayed HTR. One patient was given M antigen‐negative PRBCs in subsequent transfusions after he received 12 units of PRBCs with Hb level decreased and total bilirubin level increased. Transfusion was stopped for the other two patients after they manifested unexplained fever, soy‐sauce‐colored urine, and yellow sclera with detection of anti‐E antibodies on antibody screening for HTR. All patients were relieved FINALLY.ATR appeared in 2/230 (0.9%) patients in the HE‐PF group. The transfusion of FFP was immediately stopped with decadron and adrenalin given to ONE patient when double eyelids dropsy and urticaria in her upper extremities manifested. Transfusion was timely interrupted with decadron, hydrocortisone, and adrenalin administered to another patient when red papules developed in his forebreast and his blood pressure persistently dropped during PRBC transfusion. Their symptoms were finally relieved.P = 0.135). Blood transfusion was stopped immediately, and they were given symptomatic and supportive treatments with conditions finally in remission.Patients were diagnosed with TRAIL when acute respiratory distress or acute pulmonary edema symptoms developed within 6 h after blood transfusion. TRALI occurred in 5/319 (1.6%) patients in total, 2/230 (0.9%) patients were in the HE‐PF group, and 3/89 (3.4%) patients were in the LE‐PF group (P = 0.621). Their pressure ulcers were treated with cleanout or debridement, and they were prescribed with antibiotics. Their symptoms were alleviated before discharge. DVT occurred in 6/319 (1.9%) patients, all of whom were all in the HE‐PF group. All six patients were treated with thrombolytic therapy and cured without DVT before discharge (Table There were 5/319 (1.6%) patients diagnosed with pressure ulcers during the process of hospitalization, 3/230 (1.3%) of whom were in the HE‐PF group and 2/89 (2.2%) of whom were in the LE‐PF group (Previous studies have found several factors connected with red blood transfusion and the impact of red blood transfusion on pelvic fracture patients,High‐energy mechanisms in blunt trauma, such as traffic accidents and falls from height are two leading causes of HE‐PFs.HE‐PF patients were more likely to be diagnosed with partially unstable B1 fractures and unstable C1and C2 fractures, while LE‐PF patients were more likely to be diagnosed with stable Tile A1 and A2 fractures. The Tile classification used to classify different magnitudes of pelvic fractures in our study is based on the injury mechanism and the pelvic ring's stability. Compared with stable Tile A fractures, Tile C fractures are known for a bleeding tendency and increased blood transfusion because of their unstable properties.It has been shown that massive hemorrhage can even deteriorate under the stress of retroperitoneal hematoma and hemorrhagic shock.9/L is suggested for PC in major trauma patients with significant bleeding.Blood loss from trauma in pelvic fracture patients can lead to observed hemostatic abnormalities.Elective pelvic fixation surgeries are performed to recreate the pelvic ring's stability when the patient's trauma is controlled suitable for surgery. IF and EF can provide the best fixation stability and satisfactory effectiveness to stabilize unstable pelvic fractures.The retrieval of data from six hospitals increased the external validity, but the information bias of retrospectively obtained data was inevitable. We only considered the intervention taken from admission to discharge, while the prehospital care record was unavailable. Further study that considers prehospital care would be needed because prehospital fluid administration might impact the blood volume of patients.This study identified that patients with HE‐PFs had more severe pelvic fractures and combined injuries, and they demanded more perioperative transfusions of PRBCs, FFP, and albumin than patients with LE‐PFs. The optimal scale regression identified four independent factors positively associated with more perioperative PRBC transfusion: the presence of hemorrhagic shock on admission, Tile classification, methods of pelvic stabilization, and Hb levels on admission.


To assess if the introduction of routine pre‐operative cardiopulmonary exercise testing (CPET) in radical cystectomy has delayed surgical intervention.A prospective database of patients undergoing radical cystectomy in our local health network was maintained. A retrospective analysis of two years (2018–2020) included 38 patients. Of these, 15 patients had CPET pre‐operatively, and a direct comparison was performed.p = 0.32), with comparable rates of neoadjuvant chemotherapy (NAC) (62.5% and 64.29%). Average length of stay was 18.6 days compared with 13.87 (p = 0.16), favouring the CPET group. The CPET group also had a lower readmission rate within 30 days . Cause‐specific mortality within 90 days was 10.2% and within the study timeframe was 36.84% . Within the CPET group, eight had an anaerobic threshold (AT) of <11 ml/kg/min (range 6.3–10.5): Of these, 50% had Clavien‐Dindo complications of grade 2 or higher and the 90‐day mortality rate was 37.5% (cf. 0% in those with AT > 11 ml/kg/min in this series).The mean time from diagnosis to cystectomy was 95 days in patients who did not have CPET compared to 110 days for those who did (CPET is a valuable risk evaluation tool. This study suggested that CPET contributed to a minor non‐significant delay to surgery, however was associated with reduced length of stay and readmission rates, and was a valuable risk evaluation tool. We found that CPET AT <11 ml/kg/min is associated with higher rates of patient morbidity and perioperative mortality. Its focus is measuring oxygen uptake . If this is not possible, secondary methods  are utilised to determine AT.All patients aged 18 years and over who underwent open radical cystectomy at John Hunter Hospital from January 2018 to December 2020 were included. Pre‐operative CPET became routine for cystectomies in December 2019; CPET testing is performed on a calibrated electronically‐braked cycle ergometer, with patients wearing a 12‐lead ECG and being monitored by an exercise physiologist and medical doctor. The rate at which power increases each minute is individualised, with the aim of achieving a test duration of between 8 and 12 min. Breath‐by‐breath expired gas analysis is undertaken using a Medisoft Exp'air metabolic cart. Peak exercise capacity is defined as the rate of oxygen consumption averaged over the final 30 second epoch of the CPET. AT at our institution is determined using the Modified V‐slope method , pre‐operative haemoglobin and albumin, histopathology results and staging, time from histopathological diagnosis to cystectomy, details of pre‐operative CPET assessment, perioperative or postoperative complications, length of ICU and hospital stay, readmissions, and post‐operative survival.Ethics approval was obtained from Hunter New England Human Research Ethics Committee, a NSW Health Lead HREC and informed consent obtained from participants.p < 0.05 considered statistically significant.Comparative analysis was completed including a Kaplan–Meier survival curve, with 95% confidence intervals where indicated and 3Thirty‐eight patients were included over the two‐year retrospective study period. Overall, the mean age at diagnosis was 64 years and patients waited an average of 100.8 days from diagnosis to cystectomy. Twenty‐three patients had neoadjuvant chemotherapy (60.5%), and an additional seven had adjuvant chemotherapy. The mean albumin pre‐operatively was 35.94 g/L, and mean drop in haemoglobin from pre‐operatively to immediately post‐operatively was 23.84 g/L. The mean hospital length of stay was 16.05 days, whilst average ICU length of stay was 0.14 days. The readmission rate within 30 days was 21.05%. The overall cause‐specific mortality within the study timeframe was 36.84%, and the 90 day mortality rate was 10.2% (four patients).n = 23) and Group 2  for comparative analysis (Table p = 0.32). Notably, COVID 19 may have affected elective surgery bookings in 2020 so a separate analysis of the period between January 2018–February 2020 and March 2020–December 2020 was performed, resulting in a mean of 97.81 days and 108.7 days respectively, without statistical significance (p = 0.508).These patients were divided into Group 1 , favouring Group 2. The CPET group also had a lower readmission rate within 30 days .Both groups had comparable baseline characteristics and comparable rates of neoadjuvant chemotherapy (NAC) (62.5% and 64.29%). Average length of stay was 18.6 days compared with 13.87 (p = 0.205)  compared with 43% Group 2) at 24 months, but this was not statistically significant : Of these patients, 50% had Clavien–Dindo complications of grade 2 or higher, and the 90‐day mortality rate was 37.5% (this is compared to 0% in those with AT>11 ml/kg/min in Group 2). Of the five patients who had the lowest pre‐operative AT measurements at <9 (range 6.3–8.8), four had a Clavien–Dindo complication of II or higher (80%).Within the CPET group, the mean peak VO4We have established in this study that the introduction of CPET itself did not cause significant delays to surgery in our local health district. Patients who had CPET appeared to have a shorter length of stay and lower readmission rate. However, this change in hospital stay outcomes suggests that although the demographics of the two groups were comparable, the process of having CPET may result in some degree of selection bias; the scope of this study did not include all potential candidates considered for cystectomy, only those who proceeded to surgery. In the study period, routine CPET was still being established and prehabilitation had not yet been implemented as a formal program, although it has now been introduced to optimise high risk patients. The beneficial difference then, noting that it is not statistically significant, may be attributable to a small cohort and other confounders.In reviewing the patients who had <90‐day mortality, all were cause‐specific (metastatic bladder cancer), and all had either aggressive undifferentiated or variant pathology or were upstaged at cystectomy to at least nodal metastatic disease. This likely accounts for the slightly higher than average proportion of early mortality, 10.2% compared with ~8% quoted in the literature.Anaerobic threshold is considered the optimal predictor of outcome in intra‐abdominal surgery, with <10–11 ml/kg/min considered high risk.Given the small number of patients who had CPET done, subgroup analysis beyond overall morbidity/mortality rates was not useful; however, larger studies evaluating the survival statistics of patients with stratified AT results would be useful in further assessment of whether CPET and pre‐operative optimisation programs impacts this.Limitations of this study include its retrospective design and limited cohort size which introduce potential for bias; additional studies would be beneficial with an extended time frame including prospective data collection and a longer follow up period. During the course of this study, the effect of COVID 19 on elective surgery and pre‐operative assessment may have been a confounder in delaying time to surgery.CPET is a valuable risk evaluation tool. This study suggested that CPET contributed to a clinically non‐significant delay to surgery and may result in reduced length of stay and readmission rates. We found CPET AT <11 ml/kg/min is associated with higher rates of patient morbidity and perioperative mortality.All authors declare that they have no conflict of interest or additional sources of support or funding to declare.All included data were de‐identified, and no direct patient participation was required, but consent will be sought with future prospective data collection for further study.This research study was conducted retrospectively from data obtained for clinical purposes. It was registered and approved (identifier 2020/STE01913) with the research ethics and governance information system (REGIS).ABKL and AB conceived the study. KL researched the literature, developed the protocol, and obtained ethics approval with RC. KL drafted the manuscript and performed data analysis. AT and AB supervised the study, and AB edited and approved the final manuscript. All authors have read and approved the manuscript.


Coronavirus disease 2019 (COVID‐19) infection is considered a serious highly infectious disease caused by severe acute respiratory syndrome coronavirus 2, resulting in more than 6.27 million deaths worldwide.The study aimed to compare clinical characteristics and laboratory findings of COVID‐19 patients with complications and without complications and discriminate the important risk factors for the complications and deaths.d‐dimer), lactate dehydrogenase (LDH), C‐reactive protein (CRP), creatinine, aspartate aminotransferase, and alanine aminotransferase were done.This cross‐sectional study included 75 confirmed COVID‐19 positive patients; out of which 49 were severely‐ill cases. Analysis of all patients' clinical and laboratory information on admission including serum ferritin, thrombotic activity . By using multivariate logistic regression analysis models, elevated serum ferritin and tachycardia were significantly correlated with the increased odds of complicated COVID‐19 cases  .Lymphopenia, tachycardia, tachypnea, elevated CRP, d‐dimer, LDH, and CRP levels, which were significantly linked to the severity of COVID‐19, were the prognostic biomarkers to predict the disease severity.Lymphocytopenia,  d‐dimer), lactate dehydrogenase (LDH), C‐reactive protein (CRP), creatinine, aspartate aminotransferase, and alanine aminotransferase were done. Lymphocytopenia, tachycardia, tachypnea, elevated CRP,d‐dimer, serum ferritin, LDH, and decreased SP02 were significantly observed in cases with complicated severe acute respiratory syndrome coronavirus 2 . By using a multivariate logistic regression analysis model, elevated serum ferritin and tachycardia were significantly correlated with the increased odds of complicated COVID‐19  . Lymphocytopenia,d‐dimer, LDH, and CRP levels, which were significantly linked to the severity of COVID‐19, were the prognostic biomarkers to predict the disease severity.This study linked the prognostic biomarkers to predict coronavirus disease 2019 (COVID‐19) disease severity, hence our decision to submit it to your journal. We aimed to compare COVID‐19 patients with and without complications regarding their clinical characteristics and laboratory findings and discriminate the important risk factors for the complications and death. This cross‐sectional study was carried out in a monocentric secondary healthcare hospital in Menoufia Governorate, Egypt, during the period between May 1st and June 31st, 2021. A convenient nonprobability sample of 75 patients, who were suspected clinically and confirmed by positive reverse transcription‐polymerase chain reaction as COVID‐19 cases, was recruited. Analysis of their clinical and laboratory information on admission including serum ferritin, thrombotic activity ( The causative virus was quickly detected and was labeled as a novel coronavirus . The disease was subsequently called coronavirus disease 2019 (COVID‐19).Till May 2022, the World Health Organization (WHO) reported a global spread of 521,920,560 confirmed COVID‐19 cases, with 6,274,323 deaths.The manifestations of COVID‐19 infection vary among patients in different areas but the symptoms reported in mild‐to‐moderate nonhospitalized cases are mainly headache, loss of smell, nasal obstruction, asthenia, and ear, nose, and throat symptoms.Even though most of the patients with COVID‐19 improved after treatment, it was stated that 6.1% of the patients deteriorated into critical conditions, and those patients represented about 85% of all patients who passed away.d‐dimer) biomarkers can increase clinical efficacy, delay the progression of mild/moderate to severe/critical disease, and lowering mortality rates.In the fight against COVID‐19 disease severity and patients' mortality, the prognostic factors should be detected as early as possible, thus better management strategy could be ensured. In a recent Chinese study about predicting indicators and pathogenesis of critical COVID‐19 cases, they concluded that disease progression warning factors, including biochemical , hematological , inflammatory , and coagulation , and The routine investigations included kidney function tests, electrolytes, liver function tests, creatine kinase, LDH, complete blood count (CBC), and coagulation profile.This study aimed to evaluate the prognostic markers for COVID‐19 severity and identify the indictors for complications and mortality among those patients.22.1This cross‐sectional study was carried out in a monocentric secondary health care hospital in Menoufia Governorate, Egypt, during the period between May 1st and June 31st, 2021. A convenient nonprobability sample of 75 patients, who were suspected clinically and confirmed by positive reverse transcription‐polymerase chain reaction (PCR) as COVID‐19 cases, was recruited. Exclusion criteria included patients suspected clinically but had negative PCR results, cases with incomplete clinical and laboratory data due to either death or early discharge from the hospital, or cases with special conditions including pregnancy, cancer patients, patients under immunosuppressive treatments, patients with chronic liver disease, and patients with acute coronary syndrome. The demographic and clinical data as well as laboratory parameters were collected from the registered medical records.2.2On hospital admission, the following data were collected:A. Sociodemographic data as, age‐group in years, sex, occupation, smoking status, and source of exposure to COVID‐19 virus (if known).B. Presence of any comorbidity; hypertension, diabetes mellitus, asthma, or obesity.C. Clinical manifestations including signs and symptom of COVID‐19 disease.d‐dimer, serum ferritin, LDH, and blood grouping.D. Laboratory investigations include CBC, erythrocyte sedimentation rate, AST, ALT, CRP, urea (blood urea nitrogen), albumin, creatinine, 2.3Cases were categorized as mild, ordinary, severe, and critical cases on the basis of “The Guidance for Corona Virus Disease 2019: Prevention, Control, Diagnosis, and Management edited by the National Health Commission of the People's Republic of China.”2%) less than 93% in resting‐state; or arterial partial pressure of oxygen PaO2/oxygen concentration FiO2 ≤ 300 mmHg (1 mmHg = 0:133 kPa).” (4) “Critical cases that met any of the following findings: respiratory failure, and mechanical ventilation is required; shock occurs; or complicated with any organ failure that requires monitoring and treatment in ICU.”(1) “Mild cases had mild clinical symptoms and no pneumonia manifestations on imaging.” (2) “Ordinary cases had symptoms like fever and respiratory tract symptoms, and pneumonia manifestations which can be seen in imaging.” (3) “Severe cases that met any of the following findings: respiratory distress, respiratory rate (RR) ≥ 30 breaths/min; the oxygen saturation percentage  Noncomplicated cases group (26 patients): Patients showing mild and common symptoms are described as (1) and (2).B) Complicated cases group (49 patients): Severe or critically severe cases including patient's criteria in (3) and (4).n2/n1 as 1. Approval to direct this survey was granted by the Deanship of Scientific Research, Qassim University with Grant No.10037‐L‐1‐1‐2020.The minimum required sample size was calculated as being 52 patients (26 for each group) with a power of 0.8, effect size as 0.8, α‐error as 0.05, and allocation ratio 2.4t‐test or Mann–Whitney tests were used for comparing two groups of normally distributed or non‐normally distributed variables, respectively. Qualitative data were displayed as frequency distribution (n and %) and the χ2 test was applied for comparison. Multivariate logistic regression analysis models were performed to ascertain the influence of possible determinants on the outcome . A significant level was considered at two tailed p ≤ .05.To tabulate and analyze the data, the IBM program with Statistical Package for the Social Sciences of version 25 was used . Quantitative data were presented as mean ± standard deviation. Student 3The mean recorded age of the 75 COVID‐19 cases was 62.5 ± 13.3, ranging from 17 to 86 years. Comorbidities were reported in two‐thirds of the cases, with obesity and hypertension the most cardinal , followed by diabetes mellitus (54.7%), then asthma (25.3%). Among the studied COVID‐19 patients, 49 patients presented with severe and critical complications (65.3%). Their mean age was 63.2 ± 12.5, out of which 71% were obese, 65% were hypertensive, 59% were diabetic, 33% were asthmatic, and 51% were smokers. About three‐fourths (74%) out of the 49 complicated cases were admitted to the ICU, one‐fifth (20%) were intubated and nearly one‐third (31%) died during hospitalization (Tables p > .05). Although most of the complicated COVID‐19 patients were males (57%), but on comparison with those in the noncomplicated group (54%) there was nonsignificant difference (p = .07). Regarding the presence of comorbidities, asthma was significantly more prevalent among complicated COVID‐19 cases (33%) than noncomplicated ones (12%) (p = .04)  and elevated mean value of RR (29.04 ± 6.6) than noncomplicated group  (p < .001 for both). Moreover, the mean values of heart rate (HR), d‐dimer, CPR, LDH, and serum ferritin were significantly higher among severe/critical COVID‐19 cases  than mild/ordinary group  . Lymphocytopenia was significantly prevalent among complicated COVID‐19 cases (1.95 ± 2.15) than others (5.22 ± 2.82) (p < .001)  . The variables which were still significantly correlated with the increased odds of complicated COVID‐19 while applying the multivariable logistic regression model were elevated serum ferritin and tachycardia   . However, none of those variables were significantly associated with the increased odds of COVID‐19 mortality while applying the multivariable logistic regression model (p > .05) , asthma was significantly more prevalent among severe/critical COVID‐19 patients (33%) than mild/ordinary ones (12%). During early stages of COVID‐19 pandemic, Chinese3/μl appeared as a significant risk factor for COVID‐19 disease severity on univariate analysis. This means that hospitalized COVID‐19 cases who were not admitted to the ICU, and have a total lymphocytic count of less than 1000/μl, might be in a real need of serious intervention, even with the absence of critically severe manifestations as being in an increased risk for further deterioration of their condition as was confirmed by Zheng et al.Our results showed a significantly lower mean value of lymphocytic count between the severe/critical COVID‐19 patients group when compared to the noncomplicated COVID‐19 patients. This is in alignment with Huang et al.In the current study, most markers of inflammation in laboratory findings were increased among severely‐ill cases. The COVID‐19 infection basic pathophysiology in severe patients is related to the consequences of the cytokine storm. The presence of cytokine storm in those patients with decreased lymphocyte count may represent the uncontrolled progression of the virus observed in severe cases.d‐dimer among the complicated COVID‐19 group when compared with noncomplicated one. This result was also approved by previous studies done by Yao et al.In this study, the COVID‐19 complicated patients' group showed a significantly higher CRP, LDH, and serum ferritin than noncomplicated COVID‐19 group. This is in agreement with other studies conducted in Chinad‐dimer level between 1 and 2 µg/ml was a significant risk factor for the disease severity (OR = 11.8 [95% CI = 3.26–42.8]). Zhou et al.d‐dimer level of more than 1 μg/ml (OR 10.17 [95% CI = 1.10–94.38]). The cytokine storm leads to vascular endothelial damage, stimulating the coagulation system with inhibition of the fibrinolytic system.In this study, the univariate analysis detected that In this study, hyperferritinemia was observed in patients with the severe complicated disease on admission and significantly increased among them as compared to the mild noncomplicated patients. Also serum ferritin level was one of the significant risk factors for COVID‐19 infection severity in both the univariate and multivariate analysis. Moreover, in our univariate analysis, in‐hospital death odds were elevated in cases with higher serum ferritin levels. Similarly, Ji et al.Some limitations of this study are notably apparent. First, causality interpretation is difficult due to the utilization of a cross‐sectional study design; however, interpretation of the regression results might be of relevance. Second, internal validity could be decreased due to the convenient sampling method which is subjected to selection bias as compared to the random sampling technique.5d‐Dimer, serum ferritin, CRP, HR, lower SpO2%, and lymphopenia aid in the risk of COVID‐19 patients' assessment and adequate management.This study revealed that elevated levels of Idea conceiving, data collection, and writing the original draft: Walaa A. Fadda. Conceptualization, methodology writing, writing original draft, editing the manuscript, and conducting data analysis and management: Manal A. Al‐Batanony. Conceptualization, writing original draft, methodology supervision, and revising the drafts: Reham E. E. Aboukhalil. Conceptualization and writing – review: Heba F. Khader. Supervision, conceptualization, and revising the whole manuscript: Osamah Al Rugaie. All authors contributed to the article and approved the submitted version.The authors declare no conflict of interest.This study was conducted in accordance with the Declaration of Helsinki and approved by the Committee of Research Ethics, Deanship of Scientific Research, Qassim University . Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients to publish this paper.


To systematically evaluate the safety and effectiveness of different dosages of recombinant human interferon μg/kg IFNα1b (low dosage group) monotherapy or in combination with other drugs vs. 4 μg/kg IFNα1b (high dosage group) monotherapy or in combination with the other drugs was included. The risk of bias 2.0 evaluated the RCT's quality, and the grading of recommendations assessment, development and evaluation (GRADE) tool was used for evaluating the overall quality of the evidence. Then, a meta-analysis was performed by RevMan 5.4.  7 databases, including PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, Wanfang Database, and VIP, were searched. The search time was from their inception dates to March 28, 2022. A randomized controlled trial (RCT) of 2 P = 0.02) , three depressions sign disappearing time , P = 0.010) , and wheeze disappearing time ,  = 0.03) . There was no significant difference between the two groups in coughing disappearing time, pulmonary rales disappearing time, wheezing sound disappearing time, or adverse event rates.  A total of 13 RCTs with 1719 children were included. The meta-analysis results showed that the high dosage group was significantly shorter than the low dosage group of the duration of hospital stays , α1b, high dosage IFNα1b reduces the duration of hospital stays, the disappearance time of the three depression signs, and the disappearance time of wheeze in the treatment of bronchiolitis in children. Limited by the low quality of the evidence, the conclusions still need to be supported by high-quality studies. Compared with low dosage IFN Bronchiolitis is a lower respiratory tract disease that mainly occurs in children under 24 months. The peak age of onset ranges from 2 months to 6 months. The incidence of infants in the first year after birth is approximately 11%, and bronchiolitis is one of the leading causes of illness and hospitalization in children under one year old . UnfortuInterferon (IFN) plays an essential role during bronchiolitis, particularly for children infected with RSV . IFNs arα1B (IFNα1B), as a major antiviral subtype in the Chinese population, has attracted the attention of Chinese researchers [α1B for bronchiolitis in children has been recommended by the Chinese National Formulary [α1b for bronchiolitis in children is 2–4 μg/kg [μg/kg or 4 μg/kg in clinical practice. Some researchers believe that 4 μg/kg of IFNα1b has better efficacy [μg/kg and 4 μg/kg of IFNα1b have equivalent efficacy. Considering the safety and economic effects, 2 μg/kg IFNα1b should be promoted [Recombinant human interferon earchers . As the earchers . Therefoormulary  and the ormulary . At pres–4 μg/kg , 16. Howefficacy , 18. Othpromoted , 20.μg/kg and 4 μg/kg of IFNα1b for bronchiolitis in children, providing evidence-based evidence for clinical practice.Therefore, this study aims to evaluate the safety and effectiveness of inhaling 2 This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .clinicaltrials.gov  and the WHO International Clinical Trials Registry Platform (ICTRP) , were searched for unpublished but eligible articles.A total of 7 databases, including PubMed, Embase (Ovid), Cochrane Library (Ovid), Web of Science, CNKI, Wanfang Database, and VIP, were searched. Additionally, we used a manual search strategy to retrieve the relevant articles cited by the retrieved publications. The search time was from their inception dates to March 28, 2022. Medical subject headings combined with free text terms were used to search for eligible articles. Two clinical trial registration sites, including Population: infants under 2 years old and hospitalized with a diagnosis of bronchiolitis.Intervention/control: the high dosage group was given 4 μg/kg IFNα1b, and the low dosage group was given 2 μg/kg IFNα1b, and both were treated with nebulization. IFNα1b monotherapy or in combination with other drugs  were included.Outcomes: the primary outcome is the duration of hospital stays. The secondary outcome is based on the main clinical symptoms described in the “Expert consensus on the diagnosis, treatment and prevention of bronchiolitis (2014),” including cough disappearance time, pulmonary rales disappearance time, wheeze disappearance time, and wheezing sound disappearance time, three depression sign disappearance times, and adverse event rates.Non-Chinese and Non-English studiesInaccessible studiesNo information about the childDuplicate publicationTwo researchers selected the included RCTs back-to-back according to the inclusion and exclusion criteria and extracted the data. Cochrane risk of bias assessment tool (ROB 2.0) was used to evaluate the RCT's quality, and the grading of recommendations assessment, development and evaluation (GRADE) tool was used to evaluate the overall quality of evidence. When two researchers had opposite opinions, disputes were decided by the third researcher. The content of the literature extraction includes basic information about the literature (such as first author and year of publication); basic information about the child (such as age and course of the disease); basic information about intervention ; and research results (data of outcomes).χ2 test and I2 statistics, and the random effect model was performed for meta-analysis. Subgroup analysis was performed by monotherapy or combined therapy. Sensitivity analysis was performed by eliminating included RCTs one by one in each outcome.RevMan 5.4 statistical software provided by the Cochrane Collaboration Network was performed for meta-analysis. Relative risk (RR) and risk difference (RD) were used for dichotomous data, mean difference (MD) was used for continuous data, and 95% CIs were calculated using the Mantel–Haenszel method and the inverse variance statistical method, respectively. Heterogeneity was tested by The initial searches included 2129 RCTs. After deduplication, 927 RCTs were removed. After screening titles and abstracts, 1013 RCTs were removed. Ultimately, 13 RCTs remained after screening full texts , 22–30 .The basic information of the included RCT is presented in Chen 2018  subdividThe duration of hospital stays: 8 RCTs included 733 children [P = 0.02; I2 = 68%)   .P = 0.010; I2 = 75%)   .P = 0.38; I2 = 63%)   .P = 0.47; I2 = 83%)   .P = 0.03; I2 = 73%)   .P = 0.96; I2 = 0%)  , quality) .P = 0.59; RD = 0.00, 95%CI , P = 0.77; I2 = 0%)  , P = 0.04; I2 = 71%); when IFNα1b was treated with monotherapy, there was no statistically significant difference in hospital stay between the two groups , P = 0.17)  .α1b combined therapy or monotherapy, there was no statistically significant difference in adverse event rates between the two groups ) when eliminating Zhao 2018. The meta-analysis results of wheeze disappearing time turned into no statistically significant difference ) when eliminating Li 2019.Bronchiolitis is a lower respiratory tract infection mainly involving small airways (bronchioles). It is a common cause of illness and hospitalization in infants and young children. Severe bronchiolitis may also increase the risk of children developing asthma and continue to adulthood , 31, 32.α1b inhalation for bronchiolitis. The results showed that in the duration of hospital stays, wheeze disappearing time, and three depressions sign disappearing time, the high-dosage group is significantly shorter than the low-dosage group (P ≤ 0.05), but there was no difference between the two groups in cough disappearance time, pulmonary rales disappearing time, wheezing sound disappearing time, and adverse event rates (P > 0.05).This study included 13 RCTs with 1719 children to study the safety and effectiveness of different dosages of IFNα1b nebulized inhalation for bronchiolitis based on 24 RCTs. The study results concluded that IFNα1b nebulized inhalation is safe and effective for bronchiolitis. However, there are still some problems in this study. The first is the high heterogeneity, such as the outcome of the duration of hospital stays , and the subgroup analysis of different doses of IFNα1b did not reduce the heterogeneity. In addition, only 3 RCTs compared different dosages of IFNα1b [α1b were not further studied.Chen Can  conductef IFNα1b , 19, 30,When eliminating Li 2019 , the hetα1b was treated with monotherapy. In terms of the duration of hospital stays, the conclusions of monotherapy and when combined with other drugs are inconsistent. However, considering that there is only 1 RCT on monotherapy, it cannot be concluded that there is no statistically significant difference in the duration of hospital stays between the high dosage group and the low dosage group when IFNα1b was treated with monotherapy. A large sample, multicenter clinical research is needed to support these results.Subgroup analysis showed no significant difference between the high dosage group and the low dosage group in the duration of hospital stays and adverse event rates when IFNThe areas of lower quality are “Randomization process” and “Randomization process,” 53.85% of the RCTs did not use or used the wrong method for randomization, such as according to the order of admission, which may lead to incomparable baselines between the two groups. In addition, 92.31% of the RCTs did not use blinding or concealed allocation, which may lead to bias when giving interventions or measuring outcome data.α1b inhaling for bronchiolitis in clinical practice. However, there is not any evidence-based medical evidence. This study uses systematic reviews and meta-analysis methods to provide a reference for clinical practice.There has been controversy about the different dosages of IFNThere are some limitations to this study. First, the quality of the included RCTs is low. Only 1 RCT has a result of “Some concerns,” and the others are “High risk.” Second, most of the outcomes of this study adopt the disappearance time of disease symptoms, and the judgment criteria are subjective. Third, since none of the included RCTs mentioned the symptom classification of bronchiolitis, the disease severity was not considered in this study.α1b, the high dosage IFNα1b reduces the duration of hospital stays, the disappearance time of the three depression signs, and the disappearance time of wheeze in the treatment of bronchiolitis in children. Limited by the quality of the included RCTs, the above conclusions still need to be supported by large samples and high-quality studies.Compared with the low dosage IFN


The late Nobel laureate Elinor Ostrom envisioned a polycentric approach to mitigating climate change rather than a centralised solution. Debating about global efforts to solve climate-change problems has yet not led to an effective global treaty. Ostrom argued that instead of focusing only on global efforts, it is better to encourage polycentric efforts to reduce the risks associated with the emission of greenhouse gases. Many problems conceptualised as ‘global problems’ are the cumulative results of actions taken by individuals, families, small groups, private firms, and local, regional, and national governments. Ostrom and colleagues pointed to many examples of successfully managing a common good through interaction within a community. Energy-saving actions undertaken by individuals, families and actors at a small-scale pay off and, when multiplied, may reduce emissions globally. The incentive to achieve an individual net gain may trigger human investment decisions. Here we provide experimental support for Ostrom’s basic ideas using methods of experimental economics. By subdividing experimental populations in subgroups that approach sub-goals of mitigating simulated dangerous climate change combined with incentives, the ‘global’ solution is achieved by combined subgroup contributions exceeding the ‘global’ threshold for averting simulated dangerous climate change. Incentives from refunded saved energy motivate reaching sub-goals, as Ostrom suggested. By contrast, coercing free-riding subgroups through sanctioning at a cost fails, because sanctioning also hits fair individuals who then reduce their contributions. However, the power of polycentricity with numerous successful units can help mitigate climate change. Achieving these two goals requires COly IPCC, . NeverthHowever, Ostrom criticised . In short, the approach compares the success of groups of 9 players each to assemble the ‘global’ target sum with that of such groups subdivided in thee subgroups each assembling their subgroup target; the subgroup targets need to add up to the group target to pay off ‘globally’. Further treatments test Ostrom’s idea that incentives of refunded saved energy that subgroups are offered or sanctions of subgroups by other subgroups may help groups meeting the ‘global’ target. Although we follow the tradition of experimental economics , or the nine players are subdivided in three subgroups of three players each  Fig. , 2012. TWith treatment T3 —10 groups, or the nine players are subdivided in three subgroups of three players each  .P-values are two-tailed. Except for regression analysis we use non-parametric statistics throughout.All P = 0.83, z = −0.205, N = 10 groups, Wilcoxon one-sample test). In T2 the groups assembled significantly more than €180 on average  and more than groups in T1 . A higher percentage of subgroups in T2 reached their sub-target of €60 than randomly formed subgroups of three players in T1 .In T1 individual contributions are mostly below the fair share of €2 on average except for the last two rounds Fig. , and theThus, incentives for reaching a subgroup goal repaid eventually through savings of energy produced the ‘global’ solution in the experiment, supporting Ostrom’s Ostrom,  hypothesP = 0.0013, N1 = 30, N2 = 36 subgroups, z = −3.205, Mann–Whitney U-test). Fair contributions per player (€2) were less frequent in T1 than in T2 . Generous contributions per player (4€), however, did not significantly differ between T1 (2.711 ± 0.164) and T2  were more frequent in T1 than in T2 . Similarly, the percentage of subgroups per group investing the subgroup target of €60 averaged over all groups was slightly higher than 50% in T3 but not different from T4 . Contributions per player increased from the first half to the second half in T4  but not in T3 .When subgroups have the opportunity to impose sanctions on another subgroup (T3), at least two players of a subgroup have to select the same subgroup to be disciplined. Each player of the active subgroup has a cost of €0.50 and each player of the sanctioned subgroup has a cost of €2.00. Sanctioning was used extensively, 9.0 ± 0.937 per group during the 10 rounds, almost once per round. Sanctioning had, however, almost no effect on contributions per round as compared to T4 Fig. . ContribP = 0.16, z = −1.398, N1 = 30 subgroups, N2 = 36 subgroups, Mann–Whitney U-test; Fig. P = 0.0166, z = −2.395, Mann–Whitney U-test; Fig. Selfish contributions per player (0€) did not differ significantly between T3 (2.00 ± 0.163) and T4  were significantly less frequent in T3 (1.898 ± 0.158) than in T4 : subgroups that have contributed least have been sanctioned most. Thus, sanctioning does not equalise contributions among subgroups. The number of sanctions received is highest in the subgroups with the lowest contribution rank in a group .Figure oup Fig. . Averageoup Fig.   and then increase contributions to the next round but not significantly so , remaining on average still below €6  with contributions in the next round slightly above €6 on average  nor in contributors ranking highest per subgroup . Thus, sanctioning has only a short-term disciplining effect.Do subgroups react to being sanctioned? Contributions of subgroups that are sanctioned by one subgroup are unfair—they contribute below €6 per round . Thus, the fair contributors react to their subgroup being sanctioned, which is unfair to them. Increased contributions by sanctioned free riders are compensated by the reduced generosity of co-sanctioned fair players, nullifying any sanctioning effect at the entire-group level . Those fair players contribute less during rounds after the sanctioning T3, Fig. , with onvel Fig. . Sanctio‘The problem of averting massive climate change—or a global ‘public bad’—would be a global ‘public good’’ Sandler, . BillionWe find support for Ostrom’s hypothesis in an economic game by comparing climate mitigation at the ‘global’ level with that in a world subdivided into smaller communities. In our game, the groups of volunteers are subdivided into subgroups and, according to Ostrom’s suggestion, are provided with an incentive of repaid saved energy the closer their subgroup approaches a sub-target. Polycentric groups with incentives for subgroups reach the global target significantly more often than groups without subdivision and without incentives for subgroups. With polycentricity and incentives, subjects choose less often zero-contributions and more often the fair-share contribution. This polycentric approach is about 30 percent more successful in reaching the global target at the entire-group level.Contrary to the predictions of a dynamic evolutionary model (Vasconcelos et al., Ultimately, climate change is caused by human behaviour. Indeed, ‘one lesson from decades of research in psychology is that human behaviour is strongly embedded in communities, be it neighbourhoods, information groups, or networks of friends or professionals. These social networks may often help to convey clues for change, remove barriers to change, and provide the norms and sometimes support needed for sustainable behavioural change‘ (Huckelba and Van Lange, The overall landscape of climate governance has started to exhibit some of the characteristics of polycentricity foreseen by Ostrom , ‘that iHow can we experimentally study interactions at larger scales, such as states collaborating in mitigating climate change, even though there is always the risk of free-riding of some states on the investments of others as Ostrom mentions in several places? It is possible that some states can enforce higher investments from other states, as a simulation of climate conferences has shown in an economic experiment (Milinski et al., Supplementary Meterial