Emergency Department (ED) revisits have often been used as an indicator of medical care quality. This study aimed to quantify the frequency of ED revisits within 72 h of discharge and identify its factors among children with chronic diseases.We designed a retrospective cohort study of children with at least one chronic disease who were also under 18 years of age and had attended and were discharged from the ED at King Abdullah Specialist Children’s Hospital (KASCH-RD), Riyadh, Saudi Arabia between April 19, 2015 and July 29, 2017. The outcome measure was the frequency of ED revisits during a period of 72 h after discharge.The study included 11,057 ED discharges of children with at least one chronic disease. Their revisit rate was 1211 (11%), with 83 (6.9%) having had a second ED revisit within 72 h of ED discharge. According to ICD-10 codes, the most common causes of ED revisits were respiratory, digestive, genitourinary, symptoms, and external causes. Factors of frequent ED revisits within 72 h were young age, institutional health insurance coverage, year of new health information system (2015), external causes, and genitourinary.The rate of 72-h ED revisits after discharge of children with chronic diseases treated at KASCH-RD was relatively high, and was associated with young age, institutional health insurance coverage, year of a new health information system implementation, and external causes of ED visit. These study findings amplify the need for intervention to reduce the rate of early ED revisits among children with chronic diseases. Overcrowding in pediatric emergency departments (EDs) places a heavy burden on healthcare systems in terms of financial costs , 2 and pED visits were observed in patients of various age groups, with a large amount having been noticed in children . EarlierIn several international reports, the greater rate of ED revisits in children has been attributed to young age , 15, 18 Despite the fact that revisits to the ED are well recognized as a key for quality improvement –6, no daThis is a retrospective study of all ED discharges of children with chronic diseases under the age of 18 years who attended the ED at King Abdullah Specialist Children’s Hospital, Riyadh (KASCH-RD) between April 19, 2015 and July 29, 2017. The study obtained approval from the Institutional Review Board (IRB) at the Ministry of National Guard - Health Affairs (MNG-HA), approval #RC17/081/R.The ED records of eligible children were retrieved from the institution’s BESTCare database. In 2015, the children’s hospital implemented a new integrated health information system, BESTCare. It is a unified database that allows integration of all main hospital units: inpatient, outpatient, emergency, intensive care, and operating room. All medical documentation, medical orders, medication histories, and radiology and lab results are stored in chronological order . Housingreceived healthcare services in our facility (yes/no), year of ED visit . Patients’ ages were classified into 4 groups: < 3 years, 3 ≤ age < 6 years, 6 ≤ age < 14 years, and ≤ 14 age < 18 years old.The study data included age, gender, institutional health insurance status (yes/no), new patient or patient has not In our center the health coverage includes 3 categories: 1) Ministry of National Guard employees and their dependents who are fully covered. 2) those with private health insurance coverage and 3) those without insurance but covered exceptionally based on their case complexity. We reclassified health insurance status into two groups; institutionally insured or privately insured. In our center the emergency department is open to all emergency cases. Case that sever or need urgent admission will be admitted to our hospital regardless of their insurance coverage, or nationalities.http://apps.who.int/classifications/icd10/browse/2016/en#/XVIII.The study units of analysis are ED discharges of children with at least one chronic disease. The study outcome was the number of ED revisits within 72 h of discharge . The causes of initial ED visit/revisits were classified according to the International Statistical Classification of Diseases and Related Health Problems  code, chapters I “Certain infectious and parasitic diseases” to XXII “Codes for special purposes” . The ICDp-value (P), RR, and confidence intervals (CI) for RR. A P ≤ 0.05 was considered significant.The data analysis was performed using IBM SPSS v. 25 . Subject characteristics were illustrated as frequency and percentage Table . The mosThe KASCH-RD ED medical records of 11,057 ED discharges for children with chronic diseases were analyzed. Of the ED discharges, 1211/11,057 (11%) had a first ED revisit, and 83/1211 (6.9%) had a second ED revisit within 72 h. The median age was 4.9 (25 percentile = 2.3 and 75 percentile = 8.7 years), with 60.1% being males. Among the ED discharges, 618 (5.6%) children were admitted to the hospital. Table The most common causes at the initial ED visit were respiratory 23.6%), digestive 18.5%), genitourinary (17.7%), and external causes of morbidity and mortality (7.7%). The most common causes on the first ED revisit were respiratory (52.8%), digestive (12.6%), genitourinary (11.2%), symptoms, signs, and abnormal clinical and laboratory findings (5.3%), and external causes of morbidity and mortality (3.6%) , 3 ≤ age < 6 years , and 6 ≤ age < 14 years  compared to children with chronic diseases of age ≥ 14 years. Among children with chronic diseases, institutional health insurance coverage was associated with a higher frequency of revisits within 72 h . The risk of revisits within 72 h was higher for children with chronic diseases who visited the ED in 2015  and 2016  compared to children who visited the ED in 2017. Causes for ED visits, such as digestive diseases , genitourinary diseases , respiratory diseases , and ear diseases  were also significant predictors for a higher frequency of revisits within 72 h.The results of unadjusted and adjusted Poisson analyses of the number of revisits within 72 h after ED discharge are illustrated in Table P = 0.001), 3 ≤ age < 6 years , and 6 ≤ age < 14 years  compared to children of age ≥ 14 years. The rate of ED revisits within 72 h was higher for children with institutional health insurance than for children without health insurance . The year of implementing a new health information system (2015) significantly predicted a high rate of ED revisits within 72 h , and the following year 2016 , compared to 2017. Among children with chronic diseases, external causes of morbidity and mortality  and genitourinary  were associated with a higher rate of revisits within 72 h after ED discharge. Gender was not associated with 72-h ED revisits among children with chronic diseases.Independent risk factors for ED revisits within 72 h included age, year, institutional health insurance coverage, external causes, and genitourinary diseases  was observed among children with chronic diseases in Saudi Arabia as compared to the USA 2.7% , SingapoUSA 2.7% , Canada % was obsUSA 2.7% . It may A similar ED revisit rate was found in earlier investigations: two studies among young children with gastroenteritis  and commReducing early ED revisits at KASCH-RD must be a hospital priority to reduce unnecessary costs  and imprIn the KASCH-RD center, respiratory conditions were found to be the most frequent cause of initial ED visits. This is in agreement with Goh et al., where it reported that respiratory conditions were linked with higher ED utilization . FocusinIn this large cohort study, we noted that the rate of ED revisits decreased with age in children with chronic diseases. The greater ED revisit rate in younger children noted in the study is in agreement with earlier studies showing that children of a younger age are associated with frequent ED revisits , 15, 18.In this study, institutional health insurance coverage was found to be an important determinant of ED revisits in children with chronic diseases. In several reports, public health insurance coverage as compared with uninsured (self-pay) or privately insured has been cited as an important predictor of ED revisits. Walsh-Kelly et al.  noted thA higher rate of ED revisits in children with chronic diseases appeared during the year 2015 as compared to the more recent year of 2017. This indicates that the rate of ED revisits in the Saudi facility decreased with time. This may be due to the 2015 implementation in the KASCH-RD facility of a new computerized hospital system, BESTCare, which is a unified electronic health information system that includes a clinical decision support system. The reduction of the ED revisit rate over time could be due to implementation of a wide array of training programs to promote and evaluate the use BESTCare among physicians.Studies have shown that electronic health information systems, particularly those that incorporate clinical decision tools, have the advantage of improving the healthcare provider’s adherence to evidence-based clinical guidelines and care protocols , 28. ImpThe authors identified several limitations to the study. Although the number of ED visits studied was high, the findings were based on a single-center and retrospective study rather than a multi-center and prospective assessment of within 72 h of ED revisits. We did not record ED revisits occurring at another health facility. Furthermore, the study has not collected data on important details such as mode of arrival to the ED, number of chronic diseases, physician-related causes, and patient-related causes. Despite these limitations, to our knowledge, this study represents an initial investigation on early ED revisits and their causes among Saudi Arabian children with chronic diseases.A high rate of early ED revisits was found at KASCH-RD among children with chronic diseases, occurring frequently in one in ten children. In children with chronic diseases, higher ED revisit rates are associated with young age, institutional health insurance coverage, and causes for ED visits. Intervention could be implemented to examine whether parent education on home management, early follow-up appointment in an outpatient clinic setting, and clear discharge guidance could reduce the rate of early ED revisits among children with chronic diseases.


While gross measures of brain structure have shown alterations with increasing body mass index (BMI), the extent and nature of such changes has varied substantially across studies. Here, we sought to determine whether small-scale morphometric measures might prove more sensitive and reliable than larger scale measures and whether they might offer a valuable opportunity to link cortical changes to underlying white matter changes. To examine this, we explored the association of BMI with millimetre-scale Gaussian curvature, in addition to standard measures of morphometry such as cortical thickness, surface area and mean curvature. We also assessed the volume and integrity of the white matter, using white matter signal intensity and fractional anisotropy (FA). We hypothesised that BMI would be linked to small-scale changes in Gaussian curvature and that this phenomenon would be mediated by changes in the integrity of the underlying white matter.n1 = 52, n2 = 202). In a third dataset of (n3 = 897), which included diffusion tensor images, we sought to replicate the significant associations established in the first two datasets, and examine the potential mechanistic link between BMI-associated cortical changes and global FA.The association of global measures of T1-weighted cortical morphometry with BMI was examined using linear regression and mediation analyses in two independent groups of healthy young to middle aged human subjects (Gaussian curvature of the white matter surface showed a significant, positive association with BMI across all three independent datasets. This effect was mediated by a negative association between the integrity of the white matter and BMI.Increasing BMI is associated with changes in white matter microstructure in young to middle-aged healthy adults. Our results are consistent with a model whereby BMI-linked cortical changes are mediated by the effects of BMI on white matter microstructure. Obesity is recognised as a risk factor for dementia in the elderly population  and impaThe same is true of white matter changes. For example, obesity has been associated with greater white matter volumes in frontal, temporal and parietal lobes , as wellTo clarify these findings, the microstructure of white matter has been investigated using diffusion tensor imaging (DTI), a sensitive tool for assessing the integrity of white matter based on mapping the directionality of water movement within white matter fibres . The expHere, we sought to make use of convergent and complementary measures of gray and white matter morphometry to more clearly understand the underlying mechanisms through which global brain changes may occur in the context of obesity. It has previously been reported that subtle differences in cortical features in subjects with mild cognitive impairment and Alzheimer’s disease are driven by reduced white matter volume and white matter integrity . Based oWe tested this hypothesis using measurements of gray and white matter morphometry. Specifically, we predicted that BMI-associated changes in white matter microstructure mediated the cortical changes detectable as the increase in the degree of Gaussian curvature at the brain’s surface. While the so-called mean or extrinsic curvature of a surface depicts its extrinsic shape, i.e., the folding of the cortex, Gaussian curvature is an intrinsic feature of the surface Fig.  and may Based on previously published work, we hypothesised that obesity is primarily associated with subtle changes in the microstructure of white matter, and therefore that the measure of millimeter-scale Gaussian curvature would be a more sensitive indirect marker of subtle BMI-driven changes in white matter microstructure than mean curvature. We studied the relationship between BMI and cortical morphometric measures in three independent datasets  of healthy young to middle-aged subjects. In datasets A and B, we examined associations between BMI and T1-weighted cortical morphometry measures, including Gaussian curvature, mean curvature, surface area and cortical thickness. We extended this to assessing white matter measures: volume and signal intensity, adopted as a T1-weighted marker of white matter integrity. In dataset C, we sought to replicate significant effects established in datasets A and B, and extended our analysis by measuring FA, as a well-validated measure of white matter integrity based on DTI. Finally, across all three datasets we also conducted post-hoc mediation analyses, based on the results of the regression analyses. These were conducted to formally establish a link between BMI-linked changes in cortical and white matter measures.2 (range 19.19–38.89 kg/m2), 26 females) were scanned as part of studies conducted at the Child Psychiatry Branch of the National Institute of Mental Health, in Bethesda, Maryland, US. Scanning was approved by the institutional review board of the National Institute of Mental Health. All subjects provided written informed consent. Subjects had no history of brain injury or neurological disorder. T1-weighted scans were acquired on a 1.5 T GE Sigma scanner, using a 3D SPGR sequence with the following parameters: echo time = 5 ms, repetition time = 24 ms, flip angle = 45 degrees, slice thickness = 1.5 mm, in-plane resolution of 0.9375 × 0.9375 mm, field of view 240 mm.52 subjects (mean ± SD: age 25.44 ± 5.27 years (range 18.19–42.08 years), BMI 27.46 ± 6.11 kg/m2 (range 18.5–46.4 kg/m2), 158 females) were scanned as part of studies conducted at the Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. Scanning was approved by the National Health Service Local Research and University of Cambridge Psychology Research Committees. All subjects provided informed consent. Subjects self-reported as healthy, with no relevant medical history. T1-weighted scans were acquired on two 3 T scanners, the Siemens Trio and Siemens Verio, using an MP-RAGE sequence with the following parameters: echo time = 2.98 ms, repetition time = 2300 ms, inversion time = 900 ms, flip angle = 9 degrees, isotropic resolution of 1 mm, field of view 256 mm.202 subjects (mean ± SD: age 32.29 ± 7.72 years (range 18 – 50 years), BMI 28.45 ± 6.21 kg/m2 (range 16.48–47.76 kg/m2), 503 females) were obtained from the 2015 public release of the Human Connectome Project (HCP) (www.humanconnectome.org). This group of subjects comprised 107 monozygotic twin pairs, 116 dizygotic twin pairs and 451 fraternal siblings, from 381 families. The subjects were scanned in Washington University, St Louis, Missouri, US. A detailed list of inclusion/exclusion criteria can be found in , p < 0.01; Fig. The Gaussian curvature of the white matter surface was correlated with the intensity of white matter in both datasets (dataset A: p = 0.028, pFDR < 0.05, Fig. p = 0.0536, Fig. p < 0.05. FA was negatively associated with BMI (β = −0.0206 ± 0.0058, p = 0.004, pFDR < 0.05, Fig. t = 6.52, p < 0.0001, Fig. Gaussian curvature of the white matter surface was positively associated with subjects’ BMI (β = 0.014 ± 0.064, t = −19.4892, p < 0.0001, Fig. p = 0.05, Fig. t = −4.2793, p < 0.0001, Fig. p = 0.01, Fig. White matter signal intensity was negatively correlated with Gaussian curvature of the white matter surface (In this study we demonstrated that obesity is associated with small-scale morphometric changes in cerebral cortex and that differences in white matter integrity act as a mediator between obesity and cortical changes in three independent datasets of healthy young to middle-aged adults. While there was no consistent evidence of associations between BMI and global measures of cortical thickness, surface area or white matter volume, in all three datasets we found a consistent positive association of BMI with Gaussian curvature of the white matter surface. This was found across the entire brain and we found no evidence of region-specific effects. In keeping with our model, a mediation analysis demonstrated that the positive association between BMI and white matter surface Gaussian curvature was in turn associated with BMI-associated impairments of white matter microstructure.Associations between brain structure and BMI have been inconsistent in the literature and this may relate to the methodologies as well as the scale of the measurement , 10. We In contrast to the measure of mean curvature, which describes the degree to which the cortical surface is folded, Gaussian curvature provides a measure of the intrinsic shape of the surface , 12. StrHaving identified and internally replicated this relationship between BMI and curvature, the key question is what mechanical changes might account for it. Based on prior observations in neurodegenerative disorders , and theThe association between white matter integrity and increased adiposity as reported here may be linked to various obesity-related pathophysiological mechanisms. Obesity-related inflammation is a one strong candidate, and it is well established that obesity is associated with low-grade systemic inflammation. For example, hypertrophic adipocytes have been linked to increased secretion of pro-inflammatory cytokines, such as IL-6 and TNF-alpha. These have been shown to induce an inflammatory response in the microglia with local cytokine release –27 and aThe MRI datasets analysed in this paper differed in demographic factors, and were collected at different research sites and by different research groups. Consequently, the inclusion and exclusion criteria were not consistent across datasets. While these differences between our three groups of subjects were advantageous in demonstrating the robustness of Gaussian curvature in detecting BMI-effects across different datasets, the availability of DTI only in dataset C restricted the type of analyses we could perform. However, across all three datasets, we extracted T1 white matter signal intensity at the distance of 1 mm below the white mater surface, as an indicator of white matter microstructure, and cross-validated this measure with global FA in dataset C, as a well-established measure of white matter integrity. The reduction of white matter signal intensity is related to increased T1 relaxation time, often driven by increased white matter water content , which iIn summary, we have demonstrated a consistent increase in global Gaussian curvature at the white matter surface with increasing BMI in three datasets, including 1151 subjects in total. This effect was mediated by reduced white matter microstructure with increasing BMI. Our results suggest that BMI is associated with changes in white matter microstructure in young to middle-aged healthy adults, which is linked to changes in the intrinsic geometry of the white matter surface. We propose that Gaussian curvature can be used as a sensitive T1-weighted MRI measure for tracking the effects of obesity on cortical morphology.Supplementary infomation


Mycetoma is a chronic inflammatory process caused either by fungi (eumycetoma) or bacteria (actinomycetoma). In this retrospective study, we report epidemiologic and histopathological data of mycetoma observed in the Lome Hospital, Togo in a 25-year period (1992–2016).This is a retrospective study, over a period of 25 years, to analyze epidemiological and etiological findings of mycetomas seen in the single laboratory of pathological anatomy of the Lomé, Togo.n = 23 cases; 69.7%). Diagnosed etiologic agents were fungal in 24 cases (72.7%) and actinomycotic cases in 9 cases (27.3%). The fungal mycetomas consisted of Madurella mycetomatis (black grains) and Falcifomispora senegaliensis (black grains). The actinomycotic agents were represented by Actinomadura madurae (white grains), Actinomadurae pelletieri (red grains) and Nocardia sp. (yellow grains).A total of 61 cases were retrieved from which only 33 cases were included which where clinically and microbiologically confirmed. The mean age of the patients was 29.7 ± 1.34 and a sex ratio (M/F) of 1.5. The majority of patients were farmers (This report represents a single-center study which provides epidemiologic and histopathological data of mycetoma cases in Togo. Mycetoma is pathological processes in which fungal or actinomycotic agents of exogenous origin produce grains . They arThe West African endemic area, defined by annual rainfall ranging from 100 to 800 mm, includes Mali, Mauritania, Niger and Senegal . In thisThis is a retrospective  analysis of the database, and histopathological records of the Department of anatomical pathology at the General Hospital of Lome, patients were enrolled between 1992 and 2016 (25 years). We included all cases of mycetoma confirmed by histopathological observation of grains using a variety of histochemical stains like hematoxylin and eoisn (H and E), periodic acid Sciff’s (PAS) and Grocott’s methenamine silver (GMS) . The parThis study received approval from the head of the laboratory department to be conducted (Ref No. 08/2017/LAP/CHUSO). Since it was counting records, patient consent was not required. However, during the counting and data collection patient names were not collected in order to preserve confidentiality.n = 9 cases, 27.3%). Depending on the occupation, 69.7% (n = 23 cases) were farmers, 18.2% (n = 6 cases) traders, and 12.1% (n = 4 cases) students. The main sites were the lower limbs , including 19 cases on the feet, trunk (n = 6 cases), scalp (n = 4 cases), upper limbs (n = 2 cases) . The annual incidence was 1.3 cases. The diagnosis was made in 20 men aged 11–73 years and 13 women aged 9–70 years. The sex ratio (M/F) was 1.5. The average age of patients in our series was 29.7 ± 1.34 years, with extremes of 12 and 73 years. The majority of the patients came from the savanna region , including 14 men and 10 women, and other regions of the country (%. The ann = 16 cases), tumor (n = 10 cases), cystic (n = 2 cases) and unspecified (n = 5 cases). Diagnosed mycetomas were black (n = 24 cases); white grains (n = 4 cases); red grains (n = 3 cases); yellow grains (n = 2 cases). Diagnosed etiologic agents were fungal in 24 (72.7%) and actinomycotic cases in 9 cases (27.3%). Fungal mycetomas were all observed in savannah zones; the fungal agents consisted of Madurella mycetomatis (black grains) in 21 cases, Falcifomispora senegaliensis (black grains) in 3 cases  in 5 cases, Actinomadurae pelletieri (red grains) in 3 cases and one case of Nocardia sp. (yellow grains) were observed in the other relatively humid regions of the country (Fig. A. pelletieri; it was localization to the liver, pancreas and right colon.Clinical features were: inflammatory form with fistulae and grains (ains n =  cases; yack n = 2 cases; wfied n =  cases. DOur study shows the rarity of mycetoma because its geographical distribution excludes coastal countries such as Togo. Indeed, mycetomas are endemic on both sides of the 15th parallel north and are observed on a strip of territory from Senegal and Mauritania to the west, to the Republic of Djibouti, Somalia to the East, to Passing through Mali, Niger, Chad, northern Nigeria and Cameroon, and Sudan , called We observed a male predominance consistent with data from the literature , 9, 11. Feet represent the preferential localization of mycetomas with about 68–82.7% according to studies , 14. TheM. mycetomatis and the white grains by Pseudoallescheria boydii and the red grain by Actinomadura pelletieri; this agrees with the data of our study [In our series, five species of etiologic agents are the cause of mycetomas. In the series reported by Pitché et al., these four etiologic agents were responsible for the majority of cases , 9. Philur study , 13, 17.Indeed, Togo, which enjoys an annual rainfall ranging between 1200 and 1800 mm depending on the region, is outside the preferred zone of red mycetoma [M. mycetomatis in fungal forms in forest zone and Actinomadura madurae among actinomycoses in savannah zone. With desert advances and population movements, the classical epidemiology of mycetomas in Africa appears to be altered. Thus, every practitioner must know these conditions, because early diagnosis ensures better management and avoids historical complications.This report represents a single-center study which provides epidemiologic and histopathological data of mycetoma cases in Togo. Mycetomas are rare diseases in Togo, and our study does not allow us to map the distribution of species in our country. They are dominated by


The aim of this study was to investigate the effect of the steep Trendelenburg position (STP) with pneumoperitoneum on whole-blood viscosity (WBV) in patients undergoing robot-assisted laparoscopic prostatectomy (RALP). The study also analyzed the associations of clinical patient-specific and time-dependent variables with WBV and recorded postoperative outcomes.− 1) was recorded as systolic blood viscosity (SBV) and that at a low shear rate (5 s− 1) was recorded as diastolic blood viscosity (DBV). Systolic blood hyperviscosity was defined as > 13.0 cP at 300 s− 1 and diastolic blood hyperviscosity was defined as > 4.1 cP at 5 s− 1.Fifty-eight adult male patients  undergoing elective RALP were prospectively analyzed in this study. WBV was intraoperatively measured three times: at the beginning of surgery in the supine position without pneumoperitoneum; after 30 min in the STP with pneumoperitoneum; and at the end of surgery in the supine position without pneumoperitoneum. The WBV at a high shear rate  who had normal SBV at the beginning of surgery and 11 patients (26.8%) who had normal DBV at the beginning of surgery developed new systolic and diastolic blood hyperviscosity, respectively. The degree of increase in WBV after positioning with the STP and pneumoperitoneum was higher in the patients with hyperviscosity than in those without hyperviscosity at the beginning of surgery. Higher preoperative body mass index (BMI) and hematocrit level were associated with the development of both systolic and diastolic blood hyperviscosity in the STP with pneumoperitoneum. All patients were postoperatively discharged without fatal complications.Changes in surgical position may influence WBV, and higher preoperative BMI and hematocrit level are independent factors associated with the risk of hyperviscosity during RALP in the STP with pneumoperitoneum.KCT0003295 on October 25, 2018.Clinical Research Information Service, Republic of Korea, approval number:  This surgical position may be associated with the development of complications, such as subcutaneous emphysema, pulmonary atelectasis, and increased airway and/or optic pressure [Prostate cancer is one of the most common cancers in the male population, and its incidence gradually increases with age . Based opressure . EventuaWhole-blood viscosity (WBV) plays an important role in circulatory flow in both large and small vessels . BecauseThe aim of this study was to investigate the effect of the STP with pneumoperitoneum on WBV in patients undergoing RALP. The study also analyzed the associations of clinical variables with WBV and recorded postoperative outcomes.https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=13745). Written informed consent was obtained from all patients at our hospital who were enrolled between September 2018 and February 2019.This single-center, prospective, nonrandomized observational cohort study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital Ethics Committee . The study protocol was retrospectively/prospectively registered at a publicly accessible clinical registration site that is recognized by the International Committee of Medical Journals Editors  physical status of I or II . Exclusi− 1 propofol  and 0.6 mg.kg− 1 rocuronium ; anesthesia was then maintained using 2.0–6.0% desflurane  under medical air in oxygen. Remifentanil  was continuously infused at a rate of 0.1–0.5 μg.kg− 1.min− 1, as appropriate. The Bispectral Index™ instrument  was set between 40 and 50 to ensure appropriate hypnotic depth. Rocuronium was repeatedly infused under train-of-four monitoring (> one twitch). End-tidal CO2 was set between 30 and 40 mmHg with adjustment of the ventilator mode. Central venous pressure (CVP) was monitored using a central venous catheter  that was inserted by experienced radiologists on the day before surgery. For fluid therapy [Balanced anesthesia was performed by attending expert anesthesiologists. Induction of anesthesia was achieved using 1–2 mg.kg therapy , a basel2 gas was insufflated into the abdominal cavity  in the supine position, and patients were placed in the STP with the maximal angle (45°) of the surgical table ; this approach was routinely applied to achieve the optimal surgical view. Intra-abdominal pressure was maintained at 12–15 mmHg during surgery. At the time of peritoneal closure, the surgical position was restored to the supine position with removal of CO2 gas.Surgery was exclusively performed by expert urologists using a specific robot-assisted laparoscopic method. CO− 1) was recorded as systolic blood viscosity (SBV) and that at a low shear rate (5 s− 1) was recorded as diastolic blood viscosity (DBV) [− 1 and 9.4–13.0 cP at 300 s− 1 in male patients, based on the manufacturer’s instructions. Accordingly, systolic blood hyperviscosity was defined as > 13.0 cP at 300 s− 1 and diastolic blood hyperviscosity was defined as > 4.1 cP at 5 s− 1.WBV was measured during surgery three times via a central venous catheter: at the beginning of surgery  in the supine position without pneumoperitoneum, after 30 min in the STP with pneumoperitoneum, and at the end of surgery  in the supine position without pneumoperitoneum Table . Blood sty (DBV) . The refPreoperative factors included age, body mass index (BMI), DM, hypertension, history of current smoking, prostate cancer stage , prostatr = z/sqrt(n)) was 0.82 (|-6.234|/sqrt(58)) and 0.86 (|-6.569|/sqrt(58)), with respect to SBV and DBV. The statistical analysis was calculated using the Wilcoxon signed-rank test (one sample case), as a post hoc method, included in G*Power software 3.1.9.4 (http://www.gpower.hhu.de/). The normality of the distribution of continuous data was evaluated using the Shapiro–Wilk test. Continuous data are expressed as median and interquartile range (IQR), while categorical data are expressed as number and proportion. Serial changes in WBV and vital signs were analyzed using the Friedman’s test and the Wilcoxon signed-rank test with the Bonferroni’s post hoc method. We compared the levels of WBV and vital signs between the beginning of surgery (reference) vs. the STP with pneumoperitoneum and the end of surgery . After separation of WBV into normal viscosity and hyperviscosity, intraoperative changes in the proportions of patients with hyperviscosity were analyzed using Cochran’s Q test with the McNemar post hoc test. Incidence rates of systolic and diastolic blood hyperviscosity according to surgical position were compared using the χ2 test or Fisher’s exact test, as appropriate. The associations between clinical variables and the development of whole-blood hyperviscosity during RALP in STP with pneumoperitoneum were evaluated using univariate and multivariate logistic regression analyses. Potentially significant factors (p < 0.1) in univariate analyses were entered into multivariate forward and backward regression analyses. The values are expressed as odds ratios and 95% confidence intervals (CIs). The clinically relevant factors were chosen when multiple perioperative factors were inter-correlated. All categorical variables were modeled as dummy variables. The predictive power of independent factors for hyperviscosity were assessed using the area under the receiver operating characteristic curve (AUC). The optimal preoperative BMI and hematocrit cut-off values according to hyperviscosity at the STP with a pneumoperitoneum were determined using the AUC method. All tests were two-sided, and p < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS  and MedCalc . We used the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria for our observational study [Because of the exploratory nature of this study and the lack of a primary endpoint with anticipated effect sizes, no sample size or statistical power calculations were performed. To achieve robust effects within a reasonable interval of time, we chose to collect data from approximately 60 patients, considering the possibility of patient drop-out. The sample size was based on available data from all patients who underwent elective RALP at our hospital during a 1-year period. A post hoc power analysis revealed that a sample size of 58 was required for an expected power of 99%. The effect size r  WBC count and hematocrit level were 6.2 (5.5–7.4) ×  109.L− 1 and 42.9% (40.5–44.8%), respectively, while the median (IQR) platelet count and fibrinogen level were 205.0 (178.5–224.3) × 109.L− 1 and 254 (221–290) mg.dL− 1, respectively. With respect to lipid profiles, the median (IQR) levels of total cholesterol, triglyceride, HDL-C and LDL-C were 176 (155–198) mg.dL− 1, 88 (67–149) mg.dL− 1, 50 (42–55) mg.dL− 1, and 93 (74–120) mg.dL− 1, respectively.In the present study, all patients had ASA physical status I or II and underwent elective RALP. The median (IQR) age was 69 62–73) years and the median (IQR) BMI was 25.4 (23.1–26.4) kg.m–73 years− 1.h− 1, 0.7 (0.6–0.8) mL.kg− 1.h− 1, and 25 (13–25) mL, respectively (Table The median (IQR) surgical duration was 130 (120–145) min, and the median (IQR) levels of crystalloid infusion, urine output, and blood loss were 2.3 (1.8–3.3) mL.kgLevels of SBV and DBV significantly increased from the supine position without pneumoperitoneum (beginning of surgery) to the STP with pneumoperitoneum Table . The incn = 14) or diastolic (n = 17) blood hyperviscosity in the supine position without pneumoperitoneum (beginning of surgery) continued to show hyperviscosity in the STP with pneumoperitoneum. In patients with persistent hyperviscosity, the changes in SBV (n = 14) were as follows: 4.4 (4.2–5.1) cP in the supine position without pneumoperitoneum (beginning of surgery), 5.3 (4.9–5.5) cP in the STP with pneumoperitoneum, and 4.3 (4.1–5.3) cP in the supine position without pneumoperitoneum (end of surgery). Furthermore, in patients with persistent hyperviscosity, the changes in DBV (n = 17) were as follows: 13.5 (13.4–16.5) cP in the supine position without pneumoperitoneum (beginning of surgery), 17.1 (16.4–17.6) cP in the STP with pneumoperitoneum, and 13.5 (12.9–16.3) cP in the supine position without pneumoperitoneum (end of surgery). There were significant differences in SBV (p = 0.001) and DBV (p < 0.001) between the supine position without pneumoperitoneum (beginning of surgery) and the STP with pneumoperitoneum.With respect to changes in the prevalence rates of systolic and diastolic blood hyperviscosity during surgery Table , 12 patiWBV significantly increased from the supine position without pneumoperitoneum to the STP with pneumoperitoneum in patients with/without hyperviscosity at the beginning of surgery  . The optimal cut-off values for preoperative BMI and hematocrit were 25.8 kg.m− 2  and 43% , respectively, for hyperviscosity.With respect to systolic blood hyperviscosity in the STP with pneumoperitoneum Table , preoperp < 0.001). The optimal cut-off values for preoperative BMI and hematocrit were 25.1 kg.m− 2  and 43% , respectively, for hyperviscosity.With respect to diastolic blood hyperviscosity in the STP with pneumoperitoneum Table , preoperNearly all patients in our study were discharged on postoperative day 6 (mean ± standard deviation: 6.2 ± 0.8 days) and there were no fatal complications representative of Clavien-Dindo class I .The main finding of this study was that performance of RALP in the STP with pneumoperitoneum may contribute to a significant increase in WBV (in either SBV or DBV), which subsequently results in the development of hyperviscosity. Additionally, the surgical position change with gas insufflation may have aggravated WBV more in patients with hyperviscosity at the beginning of surgery than in those without hyperviscosity. Higher preoperative BMI and hematocrit level were significantly associated with increases in both SBV and DBV when RALP was performed in the STP with pneumoperitoneum.− 1) and DBV exhibits a low shear rate (≤ 5 s− 1) [WBV has been linked to complicated interactions among blood components, such as red blood cells, fibrinogen, and lipid profiles. Moreover, WBV is separated into SBV and DBV, based on shear rates: SBV exhibits a high shear rate (≥ 300 s 5 s− 1) , 26, 27. 5 s− 1) , 26. Not 5 s− 1) . In cont 5 s− 1) . Plasma  5 s− 1) .Many clinical studies have suggested that elevated WBV is associated with the development of cardiovascular and cerebrovascular diseases , 13, 30.The mechanism by which the WBV is increased in the STP with pneumoperitoneum remains unclear. In the present study, higher BMI and hematocrit level before surgery were significantly related with increases in both SBV and DBV in the STP with pneumoperitoneum. First, obesity has been linked to increases in hemorheological parameters, including WBV , 31. In 2 gas insufflation in the abdominal cavity  is used to achieve an optimal surgical view, but this may impair hemodynamic flow [Hematocrit is an important factor that is positively related to WBV . In the mic flow , 35, 36.There were some limitations to this study. First, because of logistical restrictions, we did not evaluate the WBV prior to surgery. Neither hemodynamic instability nor resuscitation therapy were observed before or after anesthetic induction in our cohort. Second, we did not measure the deformability of red blood cells. Because red blood cell deformability affects WBV , 29, furWe found that WBV  significantly increased, in a time-dependent manner, in patients undergoing RALP in the STP with pneumoperitoneum. The WBV reached levels indicative of hyperviscosity, but no patient showed occlusions of hemodynamic circulation, which can result from the recovery of normal WBV at the end of surgery . The patients with hyperviscosity at the beginning of surgery  seemed to be more susceptible to aggravation of WBV than those without hyperviscosity when the STP with pneumoperitoneum was performed during surgery. Therefore, changes in surgical position may contribute to changes in WBV. Higher preoperative BMI and hematocrit level were significantly associated with the development of hyperviscosity during RALP in the STP with pneumoperitoneum. An additional large-scale study may be helpful for identification of patients at risk of hyperviscosity and circulatory impairment during surgery requiring use of the STP with pneumoperitoneum.Additional file 1. Intraoperative systolic blood viscosity between patients with/without hyperviscosity at the beginning of surgery.Additional file 2. Intraoperative diastolic blood viscosity between patients with/without hyperviscosity at the beginning of surgery.


The majority of lung cancer (LC) patients are diagnosed at a late stage, and survival is poor. Circulating RNA molecules are known to have a role in cancer; however, their involvement before diagnosis remains an open question. In this study, we investigated circulating RNA dynamics in prediagnostic LC samples, focusing on smokers, to identify if and when disease‐related signals can be detected in serum. We sequenced small RNAs in 542 serum LC samples donated up to 10 years before diagnosis and 519 matched cancer‐free controls coming from 905 individuals in the Janus Serum Bank. This sample size provided sufficient statistical power to independently analyze time to diagnosis, stage, and histology. The results showed dynamic changes in differentially expressed circulating RNAs specific to LC histology and stage. The greatest number of differentially expressed RNAs was identified around 7 years before diagnosis for early‐stage LC and 1–4 years prior to diagnosis for locally advanced and advanced‐stage LC, regardless of LC histology. Furthermore, NSCLC and SCLC histologies have distinct prediagnostic signals. The majority of differentially expressed RNAs were associated with cancer‐related pathways. The dynamic RNA signals pinpointed different phases of tumor development over time. Stage‐specific RNA profiles may be associated with tumor aggressiveness. Our results improve the molecular understanding of carcinogenesis. They indicate substantial opportunity for screening and improved treatment and will guide further research on early detection of LC. However, the dynamic nature of the RNA signals also suggests challenges for prediagnostic biomarker discovery. We investigated circulating RNA dynamics in prediagnostic lung cancer (LC) samples, focusing on smokers, to identify if and when disease‐related signals can be detected in serum. The results showed dynamic changes in differentially expressed circulating RNAs specific to LC histology and stage. The dynamic RNA signals identified different phases of tumor development over time and were associated with cancer‐related pathways. ADCsadenocarcinomasBDgblood donor groupCTcomputed tomographyJSBJanus Serum BankLClung cancerlncRNAslong noncoding RNAsMAPKMAPK signalingmiRNAmicroRNAmiscRNAsmiscellaneous RNAsNSCLCnon‐small‐cell lung cancerPI3K‐AktPI3K‐Akt signalingpiRNAspiwi‐interacting RNAsRASRas signalingRNA‐seqRNA sequencingSCLCsmall‐cell lung cancersnoRNAssmall nucleolar RNAstRFstRNA‐derived fragments1et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Lung cancer (LC) is the leading cause of cancer deaths worldwide  cohort is a population‐based cancer research biobank containing serum samples from 318 628 Norwegians , locally advanced , advanced or metastatic , and unknown  . Libraries were prepared with the NEBNext Small RNA kit  and sequenced on a HiSeq 2500  as previously described  identified LC samples and matched controls for analyses. This tool enabled us to select optimal sets of control samples when there are enough controls to select from    predictions , dependent on prediagnostic time (phase 2), stage (phase 3), and histology (phase 4) . For the remaining phases, all included cases and controls were former or current smokers. For phase 2, we selected 27 LC samples matched on stages and 135 matched controls per time window.For phase 3, we selected 9 LC samples and 45 matched controls for early LC, 14 LC samples and 70 matched controls for locally advanced LC, and 18 LC samples and 90 matched controls for advanced‐stage LC. For replication analysis, we randomly resampled phase 3 samples 20 times without replacement for each time window to bootstrap the variance of the signal. In each iteration, we randomly selected new LC samples and rematched new controls. To further test the robustness of the signals, we chose 2‐year time intervals instead of 17 months. This changes sample selection in each time frame substantially.For phase 4, we used a sliding window approach to analyze prediagnostic RNA expression dynamics dependent on stage and histology. The sliding window approach is agnostic to critical time windows since it creates a continuous RNA signal trajectory. We chose 17‐month‐long windows and 2.5‐month‐long step size to provide the smallest possible window size while maintaining statistical power. Resampling for each window is analogous to the replication in phase 3. We did not have enough samples to analyze early and locally advanced SCLC and ADC separately  and was based on a broad consent from participants in the Janus cohort. The work has been carried out in compliance with the standards set by the Declaration of Helsinki.33.1n = 542) vs controls (n = 519) , suggesting a weak overall signal. We did not detect significant enrichment of known pathways.By using all LC samples  Fig. . The maj3.22FC , we identified 1400 differentially expressed RNAs in 7 time intervals with 27 LC samples and 135 controls in each interval , significantly downregulated 6–7 years before diagnosis , isomiRs (143), and mRNAs (94). The strongest differential expression signal was detected between 3 and 4 years. Forty‐six RNAs were detected in more than one time interval. 14, isomisis Fig. .Axon guidance, MAPK, Pathways in cancer, mTOR signaling, ErbB signaling, RAS, PI3K‐Akt, and p53 signaling pathway.We detected 116 significantly enriched pathways for locally advanced LC. Almost all pathways, 112, were enriched in the time frame 3–4 years before diagnosis. The most significant pathways included For advanced stage LC, we identified 936 RNAs, using 18 LC samples and 90 controls in each interval. The highest represented RNA types were mRNAs 219), piRNAs (211), tRNAs (199), and tRFs (193). The strongest signals were observed in the time periods 1–3 and 3–4 years before diagnosis, and these intervals shared 104 RNAs. A total of 205 RNAs were found in more than one interval. An isomiR (of hsa‐miR‐486‐3p) had the largest effect size and was significantly upregulated 3–4 years before diagnosis  and mRNAs (8). A similar trend was observed between locally advanced and advanced stages for 1–4 years before diagnosis. A total of 112 RNAs were shared in this time interval, consisting mostly of tRNAs (36), tRFs (27), and mRNAs (23), and also 66 pathways. Among these pathways, we identified ial Fig. .The replication using bootstrapping Fig.  and 2‐ye3.4Lastly, we further reduced LC sample heterogeneity by including histology information. For early NSCLC, we identified two strong peaks around 4 and 7 years before diagnosis using a sliding window approach Fig. ; howeverFor advanced NSCLC, we detected two signals spanning years 0–3 and years 5–9 before diagnosis. These signals were similar in RNA composition, consisting mostly of tRFs, piRNAs, mRNAs, and isomiRs. However, the year 5–9 signal had more differentially expressed miscellaneous RNAs (miscRNAs)  and cancer dormancy  in early‐stage LC and cell proliferation in advanced LC stage (e.g. EGFR)  suggest that the functional signals were mostly related to cell‐to‐cell communication  Fig. . We founFR) Fig. , (b) theet al., TGF‐beta signaling, previously linked to dormancy  or sliding window (phase 4) approaches select different samples for analysis but confirm the highly dynamic signals. All stage‐ and histology‐specific analyses showed at least two critical time windows (peaks) where LC differs from controls, and these were usually followed by time periods with no detectable signals. Peaks and troughs might potentially indicate tumor progression and dormancy.2FC) around 7 years before diagnosis in early‐NSCLC samples and 2 years prior to diagnosis in locally advanced‐ and advanced‐NSCLC samples. Another notable example is hsa‐miR‐483‐5p, which was previously found to promote metastasis of ADC . In analyses, when confounder information is critical , samples with missing information were excluded (Fig. les Fig. . This ca5This study clearly shows that LC signals can be detected in serum RNA up to 10 years prior to diagnosis. The highly dynamic signals are time‐to‐diagnosis‐, stage‐, and histology‐dependent and indicate disruption of cancer‐related pathways detectable in circulation. This is very promising for LC biomarker discovery and indicates a substantial opportunity for screening and improved treatment.The authors declare no conflict of interest.HL and TBR devised the project and gathered the samples. RL and TBR designed and coordinated laboratory work and sequencing. SUU performed analyses and drafted the manuscript. SUU, TBR, RL, and HL wrote the article in consultation with AK, ÅH, and EM. All authors provided critical feedback and helped to shape the article.Fig. S1. The distribution of LC case samples based on stage, histology, and prediagnostic time.Fig. S2. Consort figure.Fig. S3. Age of individuals.Fig. S4. Phase 1 results and the volcano plot.Fig. S5. Enriched pathways.Fig. S6. Comparison of two different time intervals.Fig. S7. Bootstrapping analysis for phase 3.Click here for additional data file.Table S1. RNAs over time and stage.Click here for additional data file.Table S2. Table of enriched pathways.Click here for additional data file.


Background: Hypophosphatemia is common during continuous renal replacement therapy (CRRT) in critically ill patients and can cause generalized muscle weakness, prolonged respiratory failure, and myocardial dysfunction. This study aimed to investigate the efficacy and safety of adding phosphate to the dialysate and replacement solutions to treat hypophosphatemia occurring in intensive CRRT in critically ill patients.Methods: We retrospectively analyzed 73 patients treated with intensive CRRT (effluent flow ≥35 ml/kg/hr) in the intensive care unit. The control group  received no phosphate supplementation. The treatment groups received dialysate and replacement solution phosphate supplementation at 2.0 mmol/L  or 3.0 mmol/L .Results: The CRRT-induced hypophosphatemia incidence was 59.0%. Correction of hypophosphatemia with phosphate supplementation changed the mean serum phosphorus levels to 1.24 ± 0.37 and 1.44 ± 0.31 mmol/L in groups 2 and 3, respectively (p = .02). The time required for correction was 1.65 ± 0.80 and 1.39 ± 1.43 days for groups 2 and 3, respectively and was significantly longer in group 2 (p = .02). After supplementation, hypophosphatemia, and hyperphosphatemia both occurred in 7% of group 2. Group 3 developed no hypophosphatemia, but 20% developed hyperphosphatemia. The serum phosphate levels in hyperphosphatemia cases returned to normal within 2.0 days (group 2) and 1.0 day (group 3) after stopping phosphate supplementation.Conclusion: Phosphate supplementation effectively corrected CRRT-induced hypophosphatemia in critically ill patients with an acute kidney injury. The use of 2 mmol/L phosphate is appropriate in patients with CRRT-induced hypophosphatemia, but a different concentration could be required to prevent hypophosphatemia at the start of CRRT. Therefo® are effective in the prevention of hypophosphatemia in CRRT patients [There are several approaches for phosphate repletion to prevent hypophosphatemia in CRRT patients. Phosphate may be administered via the oral, enteric, or intravenous route. During CRRT, through intravenous supplementation, it is not easy to maintain serum phosphorus at a stable level or to predict the change in serum phosphorus level. Recently, phosphate is mainly added to dialysate and replacement fluids . Santiagpatients ,25,26.® (phosphate 1.2 mmol/L) as dialysate and replacement fluid. However, the effluent flow rate was only 18 mL/kg/hr in their study [® was able to induce and/or maintain normophosphatemia in 88% of the patients after 72 h of CRRT treatment, and in the whole treatment period, only 4.6% of serum phosphorus determinations met the criteria for mild or moderate hypophosphatemia [Even with such phosphate repletion regimens, hypophosphatemia during CRRT cannot be completely prevented. Especially in the case of intensive CRRT with a high effluent flow rate, it is difficult to avoid CRRT-induced hypophosphatemia. Broman et al. reported that a hypophosphatemic episode did not occur when CRRT was administered with Phoxiliumir study . Pistolephatemia . In contphatemia , and henThe present study demonstrates the safety and efficacy of phosphate supplementation added to dialysate and replacement fluids to treat hypophosphatemia in patients requiring intensive CRRT. However, this was a relatively small, retrospective study. As such, the conclusions of statistical significance testing are limited. In addition, it was not possible to obtain information on the delivered dose from the EMR, and this would have been useful in comparison to the prescribed dose. Although the study demonstrated that phosphate supplementation may effectively treat hypophosphatemia once it occurs, phosphate containing solution was not administered from the initiation of CRRT, and prevention of hypophosphatemia was not demonstrated. Further, nutritional supplementation which could impact the occurrences of hypophosphatemia and hyperphosphatemia were not analyzed. To overcome these limitations, a large randomized prospective study should be conducted. In addition, this treatment approach should be applied with caution in practice.The addition of 2 mmol/L phosphate to dialysate and replacement solution effectively corrected hypophosphatemia during intensive CRRT administered with an effluent flow rate of 35 mL/kg/h and stabilized serum phosphorus levels. The present study suggests considerations for determining the optimized level of phosphate supplementation in the dialysate and replacement fluids. The use of 2 mmol/L phosphate is a valid method in hypophosphatemic patients, but a different concentration of phosphate could be more appropriate if the aim is to prevent hypophosphatemia at the start of CRRT.


Gray matter (GM) pathology is closely associated with physical and cognitive impairment in persons with multiple sclerosis (PwMS). Similarly, serum neurofilament light chain (sNfL) levels are related to MS disease activity and progression.To assess the cross–sectional and longitudinal associations between sNfL and MRI–derived lesion and brain volume outcomes in PwMS and age–matched healthy controls (HCs).q‐values <0.05 were considered significant.Forty‐seven HCs and 120 PwMS were followed over 5 years. All subjects underwent baseline and follow–up 3T MRI and sNfL examinations. Lesion volumes (LV) and global, tissue–specific and regional brain volumes were assessed. sNfL levels were analyzed using single molecule array (Simoa) assay and quantified in pg/mL. The associations between sNfL levels and MRI outcomes were investigated using regression analyses adjusted for age, sex, baseline disease modifying treatment (DMT) use and change in DMT over the follow‐up. False discovery rate (FDR)–adjusted 1‐, T2‐ and gadolinium‐LV , but not with their longitudinal changes. Higher baseline sNfL levels were associated with lower baseline deep GM , thalamus , caudate  and hippocampus  volumes. Baseline sNfL was associated with longitudinal decline of deep GM , putamen , whole brain , thalamus , globus pallidus , and GM  volumes. No associations between sNfL and MRI–derived measures were seen in the HCs.In PwMS, baseline sNfL was associated with baseline THigher sNfL levels were associated with baseline LVs and greater development of GM atrophy in PwMS. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system which presents with reoccurring and transient neurological deficits followed frequently by insidious accumulation of physical and cognitive disability.Persistent inflammation, concurrent axonal transection, and increased oxidative stress lead to a common final pathway of neuronal apoptosis and initiation of Wallerian degeneration.Neurofilament light chain (NfL) is the main scaffolding component of the axonal cytoskeleton. Multiple neurodegenerative diseases are highlighted by damage and loss of the neuro–axonal unit, processes which result in abnormally high NfL levels in CSF and in blood.Based on this background, we aimed to analyze associations between serum neurofilament (sNfL) levels with current and future neurodegenerative pathology in a heterogeneous group of persons with MS (PwMS) and age–matched healthy controls (HCs) over 5 years. In particular, we attempted to determine specific associations of sNfL with MS lesions, global brain volumes, and development of distinct pathology in the DGM, cortical and leptomeningeal structures.The study utilized PwMS and HCs that were initially enrolled in a larger prospective, case‐controlled study which examined the cardiovascular, environmental, and genetic factors in PwMS (CEG‐MS).Both at baseline and follow‐up, the PwMS underwent a full neurological examination and Expanded Disability Status Scale (EDSS) scores were derived.The MRI examinations were performed on a 3T GE Signa Excite HD 12 Twin Speed 8‐channel scanner  with an 8‐channel head and neck (HDNV) coil. There were no major MRI hardware or software changes over the follow–up period. The specific MRI acquisition parameters are provided in the Data 1, T2, and gadolinium (Gd)–enhancing lesion masks were obtained using semiautomated contouring/thresholding technique, as described elsewhere.T1 hypointensities were filled to avoid tissue misclassification.Prior to the brain volume segmentation, the Thttp://www.xinapse.com) and LMCEs were evaluated, as previously reported.The presence of leptomeningeal contrast enhancement (LMCE) was defined as post‐contrast signal intensity within the subarachnoid space which was substantially higher when compared to the brain parenchyma.The blood samples were collected at the time of the MRI examination and properly stored. Later on, the samples were sent to the University of Basel where the baseline and follow–up levels of the sNfL were derived using a validated single molecule array (Simoa) assay and quantified in pg/mL. The full description of Simoa assay is published elsewhere.χ2 test, Student’s t‐test, one‐way analysis of variance (for parametric variables), Mann–Whitney U‐test (for nonparametric variables), age–adjusted analysis of covariance (ANCOVA), and negative binomial regression accordingly. The associations between the sNfL levels and the MRI–derived lesion and brain volumes were analyzed using linear regression models where the MRI variables were set as dependent variables and the sNfL levels, age, sex, baseline DMT and change in DMT over the follow‐up were set as independent variables. Regression model–derived R2, beta (B), standard error (SE), standardized β, and P‐values were derived. All regression–model metrics are fully reported in the Data P‐values  were calculated. Q‐values <0.05 were considered statistically significant.Statistical analyses were performed using SPSS version 25.0 . The normal distribution of the data was determined using the Kolmogorov–Smirnov test. The differences between PwMS and HCs in demographic, clinical, sNfL levels, and MRI–derived outcomes were compared using P < 0.05.A secondary, post hoc analysis employed a baseline sNfL cut‐off of 30 pg/mL.t‐test P = 0.148) and in sex ratio . Within the MS phenotype, the PMS (five primary–progressive and 31 secondary–progressive MS patients) group was older and had longer disease duration when compared to the RRMS population . Furthermore, there were significant differences in the annualized relapse rate (ARR) but not in the absolute change of EDSS over the follow–up period . There were no differences in the follow–up period between the groups . The particular DMT use at baseline and change in DMT over the follow–up period are also shown in Table Detailed demographic and clinical characteristics of the study populations are shown in Table q = 0.002; and median 23.8 vs. 16.7 pg/mL, age–adjusted ANCOVA q = 0.002, respectively). Overall, there was no difference between the PwMS and HCs in the absolute sNfL change over the follow‐up .The differences in baseline, follow‐up, and longitudinal changes in sNfL levels between the HCs and the PwMS are shown in Table q = 0.172). On the other hand, the PMS group had higher sNfL at follow‐up . The PMS group had numerically greater absolute longitudinal increase in sNfL levels, compared to the RRMS group .The baseline sNfL levels were not significantly higher in the PMS group when compared to the RRMS group , caudate volume  and hippocampus volume .The differences in cross–sectional and longitudinal changes of MRI–derived lesion and brain volumes are shown in Table 1‐ and T2‐LV, lower global brain volumes, lower total DGM, thalamus, and caudate and volume at baseline . Over the follow–up period, the RRMS group lost significantly more WMV and thalamic volume when compared to PMS .When compared to RRMS, the PMS group had greater T3D‐FLAIR postcontrast imaging required for LMCE analysis was available for 88 MS patients . Seventeen out of 58 RRMS (29.3%) and 14 out of 30 PMS (46.7%) had at least one definite LMCE.1, T2 and Gd–enhancing LV . Furthermore, higher baseline sNfL levels were associated with lower cross–sectional DGM volume , thalamus , caudate  and hippocampus (β = −0.267 q = 0.015) volumes. Similarly, the baseline sNfL levels were associated with higher longitudinal loss of the WBV , GMV , and volumes of total DGM , putamen  and globus pallidus . Lastly, PwMS had significant associations between longitudinal increase in sNfL and decrease of GMV  over the follow‐up. The associations between baseline sNfL, cortical atrophy, and longitudinal change in sNfL with concurrent cortical atrophy did not survive multiple comparison correction  and . In the binary logistic model adjusted for age, sex, baseline DMT use and change in DMT over the follow‐up, baseline sNfL levels were not associated with presence of LMCE at follow‐up .Associations between baseline and change of sNfL levels with baseline and change of MRI–derived volumes are shown in Tables There was no association between baseline sNfL, longitudinal sNfL change, and any MRI‐derived volumes within the HCs population Tables  and 4.1‐, T2‐ and Gd‐LV ,  and  respectively. Baseline sNfL levels were associated also with 5‐year loss of WBV , and volumes of total DGM , thalamus , putamen  and globus pallidus . Furthermore, the longitudinal increase in sNfL was associated with longitudinal GMV . As mentioned previously, both longitudinal change in sNfL and concurrent cortical atrophy association did not survive multiple comparison correction in RRMS as well  Contrarily, the PMS only showed longitudinal associations between baseline sNfL and follow‐up Gd‐LV (exp(B)=0.829, q = 0.013) and their concurrent change (exp(B)=1.326, q < 0.001).The associations between sNfL levels and the MRI–derived volumes were additionally examined within the RRMS and PMS groups separately and are shown in Tables R2 = 0.042, q = 0.833; and Nagelkerke R2 = 0.049, q = 0.692, respectively).No associations between sNfL levels and presence of LMCE were found in neither RRMS nor PMS (Nagelkerke t‐test P = 0.005) and had longer disease duration  when compared to the <30 pg/mL group. A numerically larger portion of PwMS ≥30 pg/mL had presence of LMCE . Even after ANCOVA correction for age, sex, disease phenotype and EDSS scores, the ≥30 pg/mL group had larger T2‐LV  and smaller cross–sectional volumes of total DGM , thalamus , caudate , putamen  and hippocampus . The ≥30 pg/mL group had greater longitudinal loss of WBV , GMV , and CV   and putamen .In the post hoc analysis, the PwMS were classified based on baseline sNfL of <30 and ≥30 pg/mL Table . The ≥30P = 0.042) and were more disabled at baseline (P = 0.004). After utilizing ANCOVA corrected for age, sex, disease phenotype, and baseline EDSS, the PwMS with baseline sNfL ≥44.1 pg/mL had greater future loss of the WBV , GMV , CV , total DGM , and putamen . Similar findings were found based on the 99th percentile cut‐off (51.9 pg/mL), where the six PwMS with elevated sNfL had greater adjusted longitudinal atrophy of the GMV (P = 0.043), and putamen (P = 0.013).Based on the age–specific 97.5th and 99th percentiles HC sNfL levels, PwMS were classified with “elevated” sNfL levels, respectively. Twelve (12) PwMS had elevated baseline sNfL above the 97.5th percentile (44.1 pg/mL). There were no differences in age or sex between PwMS with elevated sNfL and the remaining 108 PwMS with baseline sNfL <44.1 pg/mL, but had more PMS patients (P = 0.017). Even after adjusting for age, the PwMS with “elevated sNfL levels” had significantly smaller baseline WBV , WMV , and all DGM structures including total DGM volume , thalamus , caudate , putamen , globus pallidus  and hippocampus . Furthermore, these PwMS had greater baseline T1 and T2 and Gd‐LV . Lastly, the individually classified PwMS with “elevated sNfL levels” had greater longitudinal atrophy in WBV , GMV , CV , total DGM , and putamen . Similarly, PwMS with elevated levels according to the 97.5th percentile individual classification had greater atrophy of the WBV (P < 0.001), GM (P = 0.004), CV (P = 0.015), total DGM (P < 0.001), thalamus (P = 0.005), putamen (P < 0.001), and globus pallidus (P = 0.037).Similarly, based on the individual age–specific classification, 12 PwMS were classified with “elevated sNfL levels” by 95th and six PwMS by 97.5th percentile cut‐off. The group with “elevated sNfL levels over 95th percentile” was significantly younger than the group with “normal sNfL levels” . Moreover, baseline sNfL levels were associated with longitudinal 5‐year change of the WBV , total DGM , thalamus , and putamen .Associations between sNfL levels and MRI–derived brain volumes were further corrected for the extent of active inflammatory activity including Gd–enhancing LV, longitudinal accrual of T1‐LV and of new/enlarging T2‐LV Table . BaselinThis study demonstrates cross–sectional and mid‐term longitudinal associations of sNfL levels and concurrent global, cortical, and DGM neurodegenerative pathology in a heterogeneous population of PwMS. More importantly, baseline sNfL levels were associated with the future longitudinal atrophy rate of WBV, GMV, total DGM, thalamus, putamen and globus pallidus. These findings remained significant despite correcting for the extent of baseline inflammatory activity, accrual of new/enlarging T2‐LV and formation of new T1 lesions. Despite the significantly higher sNfL levels seen in the PMS group, the associations between sNfL and the neurodegenerative pathology were mostly driven by the RRMS patients. Lastly, PwMS with sNfL ≥30 pg/mL had lower cross–sectional volumes and greater longitudinal atrophy rate of the global and regional volumes compared to PwMS with sNfL <30 pg/mL. Greater future neurodegenerative pathology was seen within PwMS with baseline sNfLs larger than previously determined age–specific 97.5th and 99th percentile HC sNfL levels and in analysis derived on a patient‐specific level.Axonal degeneration has been implicated as an important driver of disability accumulation.2‐LV, and Gd–enhancing lesions have been demonstrated as early as at the first demyelinating event, and are able to significantly predict conversion to clinically definite MS.2 lesion, respectively.Our findings of higher baseline sNfL levels, higher concurrent inflammatory activity, and future WBV atrophy are in line with several previous reports.Both thalamus and putamen have been highlighted as DGM nuclei with the strongest associations between baseline sNfL levels and its longitudinal atrophy rate. Since the thalamus has broad network of afferent and efferent reciprocal connections with cortical and subcortical regions, the implicated axonal dying–back pathology would be the most apparent. Furthermore, these findings are in line with previous results which demonstrated that lesioned tract disruption is associated with specific increase in regional atrophy of the putamen.Although in our analysis globus pallidus had almost twice the atrophy rate when compared to the remaining DGM nuclei, we detected weaker longitudinal associations with the baseline sNfL levels. These differences in atrophy rate and sNfL associations can be explained by the multifactorial pathophysiological mechanisms of MS neurodegeneration. For example, a recent prospective study showed that globus pallidus and its higher iron–based magnetic susceptibility signal is highly associated with greater physical disability.Admittedly, the 5‐year follow–up study design may have contributed to certain limitations in our interpretation of the biological processes. The two time–point sampling may have been too far apart to estimate the temporal relationship between the sNfL levels and the DGM and cortical atrophy. In addition to the volumetric imaging provided in this study, use of diffusion–tensor imaging or susceptibility–based imaging would provide further understanding of the multiple overlapping neurodegenerative processes. A larger PMS sample size with better characterization of both the inflammatory  and the neurodegenerative changes can provide better understanding of the sNfL utility in this particular phenotype. Furthermore, to determine the differential DMT effect on the sNfL levels and the progression of MRI brain volume outcomes is of particular clinical importance, and should be further explored. The presence of cardiovascular or other comorbid etiologies may further influence the associations between the sNfL levels and the long–term clinical and MRI–derived outcomes. Lastly, determining age–specific HC sNfL levels derived from large databases would allow better classification of abnormal sNfL levels within the increasingly older MS populations. In conclusion, the sNfL levels measured in a heterogeneous MS population are associated with higher inflammatory and future neurodegenerative pathology. The sNfL measurement is a convenient and easily accessible tool in determining MS patients who are at higher neurodegenerative risk.Dejan Jakimovski ‐ Study concept and design; analysis and interpretation; critical revision of the manuscript for important intellectual content; study supervision. Jens Kuhle ‐ Study concept and design; analysis and interpretation; critical revision of the manuscript for important intellectual content. Christian Barro ‐ Study concept and design; analysis and interpretation; critical revision of the manuscript for important intellectual content. Murali Ramanathan ‐ Study concept and design; analysis and interpretation; critical revision of the manuscript for important intellectual content; study supervision. Jesper Hagemeier ‐ Analysis and interpretation; critical revision of the manuscript for important intellectual content, Niels Bergsland ‐ Analysis and interpretation; critical revision of the manuscript for important intellectual content. Davorka Tomic ‐ Critical revision of the manuscript for important intellectual content. Harald Kropshofer ‐ Critical revision of the manuscript for important intellectual content. David Leppert ‐ Critical revision of the manuscript for important intellectual content. Zuzanna Michalak ‐ Analysis and interpretation; critical revision of the manuscript for important intellectual content. Michael G. Dwyer ‐ Analysis and interpretation; critical revision of the manuscript for important intellectual content. Ralph HB Benedict ‐ Study concept and design; analysis and interpretation; critical revision of the manuscript for important intellectual content; study supervision. Bianca Weinstock‐Guttman ‐ Study concept and design; analysis and interpretation; critical revision of the manuscript for important intellectual content; study supervision. Robert Zivadinov ‐ Study concept and design; analysis and interpretation; critical revision of the manuscript for important intellectual content; study supervision.Dejan Jakimovski, Jesper Hagemeier, Niels Bergsland and Zuzanna Michalak have nothing to disclose.Jens Kuhle received speaker fees, research support, travel support, and/or served on advisory boards by ECTRIMS, Swiss MS Society, Swiss National Research Foundation, (320030_160221), University of Basel, Bayer, Biogen, Genzyme, Merck, Novartis, Protagen AG, Roche, Teva.Christian Barro received conference travel grant from Teva and Novartis.Murali Ramanathan received research funding or consulting fees from the National Multiple Sclerosis Society, the Department of Defense, the National Institutes of Health, National Science Foundation and Otuska Pharmaceutical Development.Davorka Tomic, Harald Kropshofer and David Leppert are employees of Novartis Pharma AG, Basel, Switzerland.Michael G. Dwyer has received consultant fees from Claret Medical and EMD Serono.Ralph RH. Benedict received personal compensation from Neurocog Trials, Genentech, Roche, Takeda, Abbvie, Novartis, Sanofi and EMD Serono for speaking and consultant fees. He received financial support for research activities from Genzyme, Biogen, Mallinckrodt.Bianca Weinstock‐ Guttman received honoraria as a speaker and as a consultant for Biogen Idec, EMD Serono, Genentech, Novartis and Mallinckrodt. Dr. Weinstock‐Guttman received research funds from Biogen Idec, Genentech, EMD Serono, and Novartis.Robert Zivadinov received personal compensation from EMD Serono, Genzyme‐Sanofi, Celgene and Novartis for speaking and consultant fees. He received financial support for research activities from Genzyme‐Sanofi, Novartis, Celgene, Mapi Pharma and Protembis.Table S1. Associations between sNfL and MRI‐derived lesion and global brain volumes in RRMS and PMS subpopulations.Table S2. Associations between sNfL and MRI–derived DGM volumes in RRMS and PMS subpopulations.Table S3. Associations between sNfL levels and MRI–derived brain volumes in MS patients after correcting for inflammatory activity including baseline gadolinium lesion volume, accrual of T1‐ lesion volume and new and enlarging T2‐ lesion volume.Click here for additional data file.Data S1. MRI acquisition parameters.Click here for additional data file.


Previous studies have documented the therapeutic value of computed tomography (CT)‐guided percutaneous microwave ablation (MWA) for early‐stage non‐small cell lung cancer (NSCLC). However, few studies have focused on patients aged 80 years and older. This retrospective study aimed to evaluate the safety and clinical outcomes of CT‐guided percutaneous MWA in patients aged 80 years and older with early‐stage peripheral NSCLC.A retrospective analysis of 63 patients aged 80 years and older with cT1a‐2bN0M0 peripheral NSCLC who underwent CT‐guided percutaneous MWA was performed between January 2008 and January 2018 at 11 hospitals in Shandong Province, China.The median follow‐up time was 21.0 months. The overall median survival time was 50 months. The cancer‐specific median survival time was not reached in five years. The one‐, two‐, three‐, four‐, and five‐year overall survival rates were 97.1%, 92.6%, 63.4%, 54.4%, and 32.6%, respectively. The one‐, two‐, and three‐year cancer‐specific survival (CSS) rates were 97.9%, 97.9%, and 69.4%, respectively. The four‐ and five‐year CSS rates were not achieved. A total of 14 patients (22.2%) had local progression. The one‐, two‐, three‐, four‐, and five‐year local control rates were 88.8%, 78.8%, 70.3%, 63.9%, and 63.9%, respectively. The mortality rate was 0% within 30 days after the procedure. Major complications included pneumothorax requiring drainage (21.1%), pulmonary infection (4.2%), and pleural effusions requiring drainage (2.8%).CT‐guided percutaneous MWA is a safe and effective modality for treating patients aged 80 years and older with early‐stage peripheral NSCLC. Significant findings of the study: Microwave ablation is a safe and effective treatment for patients aged 80 years and older with early‐stage peripheral non‐small cell lung cancer.What this study adds: As a result of our findings, more older patients with early‐stage peripheral non‐small cell lung cancer may be eligible for treatment and may thus have a better prognosis.Primary lung cancer remains the leading cause of cancer‐related death among men and women.This retrospective study was approved by the Institutional Review Boards of each of the following 11 hospitals: Shandong Provincial Hospital Affiliated to Shandong University, Qilu Hospital of Shandong University, 960 Military Hospital of China, Taishan hospital affiliated to Taishan Medical College, Taian Hospital of Traditional Chinese Medicine, The People's Hospital of Cao County, Feicheng Hospital of Traditional Chinese Medicine, Shouguang Hospital of Traditional Chinese Medicine, Liaocheng Tumor Hospital, Dezhou People's Hospital, and Dezhou Tumor Hospital. The requirement for informed consent was waived, and the study was conducted according to the Declaration of Helsinki.The clinical records of patients with lung tumors who underwent MWA as their initial treatment in one of the hospitals mentioned above were reviewed. Patients (i) with stage I and lymph node‐negative IIa pathologically confirmed NSCLC; (ii) aged ≥80 years; (iii) with peripheral tumors; (iv) without medical history of other malignant tumors; (v) who refused to undergo alternative surgeries and (vi) with an Eastern Cooperative Oncology Group performance status of 0–2, and 7, whose length of follow‐up was at least six months, were eligible.For accurate clinical staging, all patients were recommended to undergo a whole‐body positron‐emission tomography‐computed tomography (PET‐CT) examination. If PET‐CT was not possible (such as for economic reasons), then enhanced craniocerebral magnetic resonance imaging, enhanced thoracic and abdominal CT, and whole‐body bone scan were suggested. The clinical staging was based on the Union for International Cancer Control TNM, eighth edition.The machine used for imaging guidance and monitoring was either a GE LightSpeed 16 Slice CT (GE), a Siemens SOMATOM Sensation 64 CT (Siemens), or a NeuViz 16 Platinum CT (Neusoft). The MTC‐3C microwave ablation system , ECO‐100A1 microwave ablation system , or KY‐2450B microwave ablation system  was used. The main frequency was set to 2450 GHz, and the output power was 0–100 W . The microwave antenna had an effective length of 100–180 mm and an outside diameter of 15–18 G, with a 15 mm active tip. The microwave antenna also had a water circulation cooling system to reduce its surface temperature.Local anesthetic agents along with pre‐emptive analgesic agents were administered to patients. Pre‐emptive analgesia consisted of 10 mg of morphine and 10 mg of diazepam administered 30 minutes before treatment and 50 mg of flurbiprofen axetil administered 15 minutes before MWA treatment. None of the patients in this study required general anesthesia. The ablation power of the microwave generator was set at 60–80 W, and the ablation time was set to 20 minutes. Once patients were satisfactorily anesthetized, the microwave ablation antenna was inserted into the bottom of the tumor using CT‐guidance. A single antenna was used for tumors ≤3.0 cm in diameter, and two antennas were used simultaneously for tumors >3.0 cm in diameter.et al.Treatment of a tumor with ablation is considered a technical success when the tumor is treated according to the protocol and is determined, at the time of the procedure, to be entirely overlapped or encompassed by the ablation zone plus an ablative margin.Complications were assessed according to the standards drafted by the International Working Group on Imagine‐Guided Tumor Ablation in 2014.The data were analyzed using SPSS for Windows Version 19.0 . Survival curves were constructed using the Kaplan‐Meier method.n = 14) or had cancer that was deemed inoperable (n = 49). The three commonest comorbidities were hypertension, coronary artery heart disease, and chronic obstructive pulmonary disease (COPD)  were enrolled in this study; subjects either refused to undergo surgery  that were completely ablated remained stable until the end of follow‐up Fig . One 80‐The median postablation follow‐up time was 21.0 months (range: 6–70 months). Seven patients died from noncancer‐related causes, while nine died of tumor progression.The median OS was 50.0 months . The estimated one‐, two‐, three‐, four‐, and five‐year OS rates were 97.1%, 92.6%, 63.4%, 54.4%, and 32.6%, respectively .The mortality rate was 0.0% within 30 days after MWA. The major complications in this study included pneumothorax requiring catheter drainage, pleural effusions requiring chest tube placement for drainage, and pulmonary infection. The overall incidence of pneumothorax requiring drainage was 21.1% , but no clear etiological evidence was obtained; the patients' symptoms were alleviated after treatment with empirical antibiotics. One patient with pulmonary cavitation at the ablation site developed pulmonary aspergillosis six months after the procedure that was treated and cured with voriconazole treatment. None of the patients had massive hemoptysis or thoracic hemorrhage requiring blood transfusion. The incidence of pleural effusions requiring drainage was 2.8% (2/71), and the incidence of In this study, none of the procedures were interrupted owing to complaints of pain. The patients developed the following side effects: pain, postablation syndrome, and asymptomatic minor bleeding or fluid accumulation on CT. Only three patients experienced mild pain at the puncture site for more than one month. The pain experienced by the other patients disappeared within one week. Five patients developed postablation syndrome characterized by fatigue, general discomfort, and anorexia. The symptoms disappeared after three days of treatment with dexamethasone. CT obtained 24 hours after each MWA session showed that almost all patients had pleural exudation on the affected side, and some also had contralateral pleural exudation that did not require puncture or catheterization.et al. compared the clinical outcomes of patients with inoperable T1‐2N0M0 NSCLC treated with stereotactic body radiation therapy (SBRT) to untreated patients.The possibility that patients with early NSCLC will not receive any treatment increases with age.et al. published a retrospective study of 193 patients with NSCLC aged over 75 years who received SBRT treatment.SBRT is the standard of care for medically inoperable patients with early‐stage NSCLC.et al. reported that they successfully performed percutaneous lung RFA in a patient with a forced expiratory volume in one second (FEV1) of <0.8 L/s.et al. found that despite the thermal effects in the lung surrounding the tumors, there were no deleterious effects on pulmonary function.et al. found that the carbon monoxide diffuse capacity of patients decreased by 12% after SBRT.Percutaneous pulmonary thermal ablation is a relatively safe and minimally invasive treatment. There are almost no absolute contraindications except for irreversible coagulation dysfunction or thrombocytopenia. In some medical institutions, the treatment is offered as an outpatient procedure. Patients with pretreatment pulmonary dysfunction may experience temporary exacerbation of respiratory symptoms after ablation and require oxygen therapy lasting one day to three weeks.et al. found emphysema as a risk factor for pneumothorax requiring catheter drainage after MWA.Aspergillus infection in the current study is consistent with that reported by Huang et al. (1.44%).The 30‐day mortality rate in the current study was 0.0%, which was consistent with those reported in previous studies.This study had several limitations: (i) it used a small sample size; (ii) it was retrospective in nature; (iii) data on factors that could influence outcomes were unavailable; and (iv) multiple devices were used by multiple operators.In conclusion, MWA is a safe and effective treatment for patients aged 80 years and older with early‐stage peripheral lymph node‐negative NSCLC. The results of this study support the use of MWA as a treatment in older patients who may otherwise be left untreated, thereby leading to improved outcomes in these patients. Additional studies, including well‐designed and sufficiently powered randomized trials, are necessary to further confirm our results.The authors declare that they have no competing interests.


Grain yield was lower under N90 than under N150 in DSR by 11–18%, whereas the difference was not significant in SSR. Grain yield under N0 was 36–63% lower in DSR than in SSR. There was a significant relationship between percentage change in grain yield comparing N90 to N150 with grain yield under N0. Furthermore, it was observed that grain yield under N0 was not significantly associated with growth duration but was closely associated with daily grain yield under N0, and the relationships of daily grain yield under N0 with seasonal average daily mean temperature and solar radiation were not significant. These results indicate that response of grain yield to reducing N rate was more sensitive in DSR compared to SSR due to lower soil N productivity. Growth duration and climatic conditions did not explain the difference in soil N productivity between DSR and SSR. The findings of this study should encourage more research into comparing the inherent traits of plants, especially the morphology and physiology of the root system, between DSR and SSR.Reducing N rate without sacrificing grain yield is crucial for sustainable rice production in China. In this study, field experiments were conducted in 2016 and 2017 to determine whether the response of grain yield to reducing N rate varied between double-season rice (DSR) and single-season rice (SSR). Three N rates were applied for each rice crop, i.e. 150 kg ha In the past several decades, rice yield has more than tripled in China as a result of the development of new cultivars and improved crop management practices2. This increase in rice yield has been important for ensuring food security in China. However, at the same time, fertilizer consumption in China has had an almost linear increase, especially for nitrogen (N) fertilizer3. The average N application rate for rice production in China at present is 180 kg ha−1, which is about 75% higher than the world average5. The high N rate has caused substantial environmental costs including enhanced N deposition, soil acidification, and surface water eutrophication8. Therefore, reducing the N rate without sacrificing grain yield is necessary for sustainable rice production in China.Rice is the staple food crop for about 65% of the population in China9. Improving soil fertility is an effective way to achieve high inherent soil productivity and consequently reduce the dependence on external fertilizer inputs in rice production10. In addition to the soil conditions, the inherent soil productivity also can be affected by the crop. For example, Huang et al.11 observed that inherent soil N productivity (i.e. grain yield without N application) was increased with the development of new rice cultivars in China.The capacity of productivity in a soil is referred to as inherent soil productivity and can be expressed by the actual crop yield without fertilizer inputshttp://ricestat.irri.org:8080/wrs). There are two rice cropping systems in this province: (1) double-season rice (DSR) cropping with early-season rice (ESR) grown from March (sowing) to July (harvesting) and late-season rice (LSR) grown from June to October; and (2) single-season rice (SSR) cropping from April to September. Growth duration is shorter in DSR compared to SSR. This difference in growth duration can result in shorter duration of soil N uptake and consequently may cause lower soil N productivity in DSR than in SSR. Moreover, climatic conditions during growing-seasons are also different between DSR and SSR. In general, seasonal average temperature and solar radiation are lower in DSR than in SSR, because ESR and LSR have lower temperature and solar radiation than SSR during the early and late growth periods, respectively. These differences in temperature and solar radiation may lead to slower crop growth and hence lower soil N productivity in DSR compared to SSR. The potentially different soil N productivity resulted from differences in growth duration, and climatic conditions may further lead to different N responses between DSR and SSR, but no studies have been conducted to confirm and clarify these differences.Hunan province is one of the major rice-producing provinces in China and contributes more than 10% of total rice production  in two years. Our objectives were (1) to determine whether the response of grain yield to reducing N rate is different between DSR and SSR, and if so, (2) to identify the factors that contribute to the difference in N response between DSR and SSR.Average daily mean temperatures during early and late rice-growing seasons were lower than that during the single rice-growing season by 1.8–4.1 °C in 2016 and by 1.1–3.2 °C in 2017 Fig. . In 201612. High temperatures shorten the growth duration and vice versa. However, in this study, the shorter growth duration in ESR and LSR than in SSR was not related to temperature because, as mentioned above, the temperature was lower during early and late rice-growing seasons than during the single rice-growing season. Therefore, the difference in growth duration between DSR and SSR should be mainly attributed to different genotypes.Growth duration from transplanting to maturity was shorter in ESR and LSR compared to SSR by 18–24 d in 2016 and by 23–26 d in 2017 Fig. . It is wGrain yield was significantly affected by rice crop, N rate, and their interaction Table . In gene−1 increase in grain yield under N0. These findings support results of previous studies suggesting that improving soil N productivity is an effective way to reduce the dependence of external N inputs in rice production11. More importantly, the results of this study suggest that the magnitude of the potential of reducing N rate may be smaller in DSR than in SSR due to lower soil N productivity.These results indicate that response of grain yield to reducing N rate was more sensitive in DSR (ESR and LSR) compared to SSR. This different N response could be related to the difference in soil N productivity (grain yield under N0) between DSR and SSR, which was significantly lower in ESR and LSR than in SSR by 38–45% in 2016 and by 36–63% in 2017 Fig. . Consist14. The findings of this study should encourage more research into comparing the morphology and physiology of the root system between DSR and SSR. Such research would provide useful information to improve soil N productivity and consequently reduce the dependence of external N inputs in rice, especially for DSR.Similar to the grain yield under N0, daily grain yield under N0 was significantly lower in ESR and LSR than in SSR by 25–29% in 2016 and by 19–53% in 2017 Fig. , and the16, but further studies are required to confirm this hypothesis. In addition, our study has potential limitations that need to be acknowledged. First, the experiment was conducted on only one soil type. Second, only one cultivar was used for each rice crop. Therefore, more experimentation should be done on different soil types with various rice cultivars to obtain broader results.Perhaps also interestingly, in contrast to the grain yield under N0, increase in grain yield with N fertilization was generally higher in ESR and LSR than in SSR Fig. . This meDSR had lower soil N productivity than SSR. As a result, response of grain yield to reducing N rate was more sensitive in DSR compared to SSR. Growth duration and climatic conditions did not explain the difference in soil N productivity between DSR and SSR.−1, total N = 1.50 g kg−1, total P = 0.61 g kg−1, total K = 7.92 g kg−1, NaOH hydrolysable N = 179 mg kg−1, NaHCO3 extractable P = 16.2 mg kg−1, and NH4OAc extractable K = 102 mg kg−1. The soil characteristics were determined based on samples taken from the 0–20 cm layer, with the methods described by Bao17.Field experiments were conducted in a farmer’s field in Yongan Town , Hunan Province, China, in 2016 and 2017. The soil of the field was a clay type with the following properties: pH = 6.26, organic matter = 44.3 g kg−1 , 90 kg ha−1 (N90), and 0 kg ha−1 (N0). Treatments were arranged in a split-plot design with rice crops (DSR and SSR) as main plots and N rates as subplots. The experiment was replicated six times and subplot size was 20 m2.Two rice cultivars, Zhongzao 39 and Y-liangyou 1, were used in this study. Zhongzao 39 was grown in early and late rice-growing seasons, while Y-liangyou 1 was grown in the single rice-growing season. These two cultivars were selected because they have been widely grown by rice farmers in the study region. Three N rates were applied to each rice crop , i.e. 150 kg haRice crops were established according to locally recommended practices. Pre-germinated seeds were sown in a seedbed. For DSR, 25- and 15-day-old seedlings were transplanted on 22 April and 21 July in the early and late seasons, respectively. Transplanting was done at a hill spacing of 20 cm × 16.7 cm with three seedlings per hill. For SSR, 25-day-old seedlings were transplanted on 4 June. Transplanting was done at a hill spacing of 20 cm × 20 cm with two seedlings per hill.2O5 ha−1 as basal) and potassium  were applied in all subplots. All fertilizers were manually broadcasted and incorporation was made only for basal fertilization. The experimental field was kept flooded (5–10 cm) from transplanting until 7 days before maturity, when the field was drained. Insects and diseases were intensively controlled by chemicals to avoid yield loss.N was applied in three splits: 50% as basal (1 day before transplanting), 30% at early-tillering (7 days after transplanting), and 20% at panicle initiation. Phosphorus  were calculated.Daily mean temperature and solar radiation during rice-growing seasons were measured using a Vantage Pro2 automatic weather station . Growth duration was recorded as number of days from transplanting to maturity. Grain yield was determined from a 5-mStatistical analysis was performed in Statistix 8.0 . Data were analyzed using analysis of variance and linear regression analysis. Means of treatments were compared based on the least significant difference (LSD) test at the 0.05 probability level.