Fluorine accelerated the process, resulting in near-complete back-replacement of albite within 1 day. These findings reveal that potassic alteration can be triggered by Na-rich fluids, indicating that pervasive sequential sodic and potassic alterations associated with mineralization in some of the world’s largest ore deposits may not necessarily reflect externally-driven changes in fluid alkali contents. Here, we show that these reactions are promoted at the micro-scale by a self-evolving, kinetically-driven process; such positive feedbacks between equilibrium and kinetic factors may be essential in driving pervasive mineral transformations.The dynamic evolutions of fluid-mineral systems driving large-scale geochemical transformations in the Earth’s crust remain poorly understood. We observed experimentally that successive sodic and potassic alterations of feldspar can occur via a single self-evolved, originally Na-only, hydrothermal fluid. At 600 °C, 2 kbar, sanidine ((K This paper reveals that potassic alteration can be triggered by Na-rich fluids, indicating that pervasive sequential sodic and potassic alterations associated with mineralization in some of the world’s largest ore deposits may not necessarily reflect externally-driven changes in fluid alkali contents. In hydrothermal ore deposits, the orebody represents only a tiny volume within fluid–rock systems that are 10’s to 100’s of km3 in scale. Many large deposits, in particular Iron Oxide Copper Gold (IOCG)2 and Porphyry Copper-Gold3, are associated with extensive alteration halos6 that form as a result of thermodynamic disequilibrium between rock and fluid. Since Na is the most abundant cation in most deep fluids, many of the characteristic mineral reactions are driven by alkali  exchange. The evolution from sodic to potassic alteration is a key feature of IOCG deposits. The current consensus is that this is caused by changing chemical and/or physical conditions7, e.g. cooling; decompression boiling; decreasing water-to-rock ratio; and hence can be well approximated as a (near–) equilibrium system8. However, recent progress in our understanding of the mechanisms of fluid-driven mineral reactions has highlighted the significance of kinetic factors and local equilibrium in controlling the evolution of fluid-mineral systems9. Interfacial fluids at fluid–mineral boundaries control reaction kinetics and mineral stability, and hence the complex feedback between fluid flow, reaction progress, and reaction-induced porosity is a key driver of crustal-scale fluid-rock interaction13.Fluid–rock interactions during metasomatic and/or hydrothermal processes control the rheology, porosity structure, and element redistribution within the Earth’s crust15. Pioneering experiments investigated the microstructural and chemical evolution of feldspars under hydrothermal conditions19, and concluded that the reactions proceeded via a fluid-driven interface-coupled dissolution-reprecipitation (ICDR) reaction mechanism, but the products of the reaction were broadly in-line with predictions from equilibrium thermodynamics. We hypothesise that the widespread temporal and spatial association between sodic and potassic alteration may be facilitated by an interplay of kinetic and equilibrium thermodynamic factors at the fluid-mineral interface. Therefore, we examined the alteration of a mixed Na-K-feldspar (sanidine) in an originally Na-only hydrothermal fluid (NaCl or NaF) in closed system experiments at isothermal, isobaric conditions.Since feldspars make up more than 50% of Earth’s crust, their complex compositions and textures can shed light on the thermal and alteration history of the crustIn this work, we observed a remarkable successive sodic and potassic alteration of sanidine rather than the expected albitisation, and discovered that the replacement kinetics increased dramatically in F-rich systems. Based on characterisation of the reaction products and thermodynamic modelling of the fluid–mineral interaction, we demonstrate that at the micro-scale, sequential sodic and potassic alterations can be driven by Na-rich fluids , and is promoted by a self-evolving, kinetically-driven process.0.62(1)Na0.33(1)Ca0.042(6)AlSi3O8   and IOCG deposits .We reacted sanidine, K0.62Na0.331)0.62(1)NaThe main reaction products are albite and/or K-feldspar for both NaCl and NaF solutions Fig. . Small aIn NaCl-solutions, the overall reactions proceeded through two stages. Stage I: an albite rim replaces the outermost part of sanidine Fig. . There c24. Here we aim to predict the system evolution under equilibrium conditions, and then use these predictions to identify potential kinetic effects that may explain the experimentally observed sequential sodic and potassic alterations. Equilibrium thermodynamic calculations are challenging since our experiments involve reactions between a complex electrolyte solution with evolving composition and mineral solid solutions characterised by a miscibility gap ; green solutus line) in equilibrium with a given solid solution composition (X(Ab); red solidus line). In the presence of a Na+-rich fluid  >0.85), the equilibrated solid is an albite-rich feldspar  of 0.85, a peritectic point is reached where the aqueous phase co-exists with two solid solutions: albite with X(Ab) = 0.88, and K-feldspar with X(Ab) = 0.35  decreases slightly below 0.85, the Na content of the equilibrated solid solution decreases dramatically, forming a K-feldspar with X(Ab) ≤0.35  of 0.13–0.22) feldspars can co-exist with Na-rich aqueous solutions  0.72–0.83; Fig. First, we examined the fractionation of Na and K between feldspar and hydrothermal solution under static thermodynamic equilibrium conditions. All thermodynamic calculations were performed with the GEM-Selektor software package, as it has been demonstrated that this package can effectively model such complex thermodynamic conditions27 . At 600 27 . The Lippar Fig. . At a X. Three different equilibrium scenarios were considered in terms of solution used, i.e. pure H2O, NaCl-H2O and NaF-H2O  formed at the peritectic point. The NaF solution showed a similar evolution history, but the equilibrium peritectic point was reached at lower sanidine/water ratio  = 0.85. These predictions are consistent with previous experiments18, whereby an Ab60Or40 feldspar was replaced by coarse-grained, co-existing albite and K-feldspar upon reaction with H2O/HCl solutions .Hence, the equilibrium simulations show that unless sanidine dissolves congruently and buffers fluid composition Fig. , it shouOur experiments, however, display different final product compositions and textures  water. We observed sharp interfaces with large contrasts in 18O/16O isotopic composition between parent sanidine (18O/16O < 0.003) and albite/K-feldspar  and texture (including porosity) of the newly formed feldspars can evolve rapidly (hours) when in contact with a fluid at 600 °C.The formation of biotite, fluorite and ilmenite co-existing with albite tallies with the complete dissolution of sanidine releasing the minor amounts of incorporated Ca, Ti and Fe. The sharp boundaries between sanidine and albite/K-feldspar and the pseudomorphic replacement are characteristic of ICDR reaction mechanismpar Fig. –6. This +/Na+ ratio relative to the bulk solution; however, albite formed first, in accordance with the initial bulk fluid composition  reaction-induced porosity , nucleation starts on the outside of the grain, and the daughter feldspar composition is consistent with the bulk fluid chemistry. However, each reaction then proceeds beyond the point of bulk saturation for each phase: albite replaces sanidine to an extent where the bulk solution becomes oversaturated with respect to K-feldspar, but undersaturated with respect to albite. This process then repeats itself, with nucleation of a K-rich feldspar replacing albite on the outside of the grain, leading to near-complete replacement of the earlier formed albite. We conclude that the back-reaction responsible for K-feldspar formation is the result of kinetic processes that prevent a swap in the composition of feldspar at the reaction interface: nucleation takes place at the interface between grain and bulk fluid, but dissolution and growth dominate at the reaction interface.Our experiments reveal that sequential sodic and potassic alterations can be driven by a self-evolved system, whereby the overprinting of sodic alteration by potassic alteration is a kinetically triggered process without any K-input or other externally induced changes in pressure, temperature, or fluid chemistry. We further discovered that F facilitated the process, most likely by lowering the activation energy required to break Si-O and Al-O bonds to increase feldspar dissolution rates.Moreover, we suggest that such kinetically controlled processes may be responsible for widespread grain-scale feldspar alteration in nature (e.g. Rapakivi textures), and that the positive feedback between this grain-scale mechanism and external physical and chemical drivers could be a key mechanism explaining the pervasive nature of successive sodic and potassic alteration associated with some of the World’s most valuable ore deposits.33. However, an external fluid-driven ICDR process was recently suggested to account for these textures34. Plümper et al.10 describe one ternary feldspar grain from the Larvik batholith, Norway, that shows a similar texture as in our experiments, with pristine feldspar replaced by porous albite, which is then further replaced by K-feldspar . They propose that these textures result from a fluid-driven mineral reaction. The F-rich fluid inclusions associated with some rapakivi granites  indicate a link between high F hydrothermal fluids and Rapakivi feldspar, consistent with the increase in the kinetics of feldspar replacement observed in our experiments. Altogether, these observations show that the Rapakivi zonation textures can form in a self-evolved hydrothermal system.At grain scale, feldspar textures such as Rapakivi  or anti-rapakivi feldspar (plagioclase mantled by K-feldspar) are typically believed to form via a magmatic mixing process20 and most IOCG deposits37 are associated with large-scale (km to 10’s of km) sodic alteration overprinted by potassic alteration38. Understanding the dynamic evolution of hydrothermal fluids in these alteration halos is the focus of numerous studies aiming to define the sources of metals, as well as identifying geochemical and mineralogical indicators for guiding mineral exploration40. In general, successive alteration styles are explained as reflecting either (i) changing compositions of fluids over time, as a result of on-going fluid-rock interactions and mineral dissolution and precipitation38; (ii) temperature changes in externally-derived convective systems42; (iii) Na-addition via interaction with evaporite-bearing wall rocks43; or (iv) magmatic unmixing of H2O-CO2-NaCl ± CaCl2-KCl fluids caused by decreases in temperature and/or pressure38. One sodic-potassic alteration zonation example is the Butte porphyry system21. In the K-feldspar alteration envelope, the X ranges from 0.77 to 0.85 for a hydrothermal fluid at 400-840 °C21. These fluid compositions are typical for magmatic fluids, that are originally rich in NaCl44, as Na+ and Cl- are the most common cation and anion in deep hydrothermal fluids45. Thermodynamic modelling shows that these fluids lie near the composition of a fluid equilibrated with albite and K-feldspar  ~0.85 at 600 °C; Fig. X, a small decrease of which would result in the formation of K-feldspar. However, thermodynamic modelling suggests that potassic alteration in such a steady state system would be limited, and would feature co-existence of albite and K-feldspar, contrary to field observations of early albite and late potassic alteration. Our experiments reveal that kinetic factors acting at the reaction interface may be important in forming potassium alteration zones surrounding and/or above the sodic alteration zone in such systems. The energetic barriers that need to be overcome to change from K-feldspar nucleation to albite nucleation effectively result in the formation of K-feldspar even past the point where the fluid at the reaction front becomes supersaturated with respect to albite, as a result of increasing Na/K ratios caused by K-feldspar precipitation. This maintains a high level of disequilibrium at the reaction front, which in turns contributes to pervasive mineral replacement.Many ore-forming systems, including some porphyry Cu41, and sodic alteration followed by potassic alteration can happen even in closed systems.We show that K-feldspar can form from NaCl-rich fluids, i.e., small changes in fluid compositions can cause a change in fluid saturation from albite to K-feldspar . Our results show that the internally and externally driven factors (predictable using equilibrium thermodynamics) at the macro-scale, may contribute to explaining the widespread occurrence of albitisation, as well as the common occurrence of potassic alteration overprinting this sodic alteration. It is important to note that the nano-scale factor is related to nucleation and growth at the fluid–mineral interface, and is controlled not only by external physical parameters such as pressure and temperature, but also by fluid composition, in our case the nature of halide (Cl versus F). These dynamic processes remain extremely difficult to assess on a theoretical basis, which requires further experiments as being critical in defining the mechanisms and kinetics of fluid-induced mineral reactions in the Earth’s crust.Our result can explain the pervasive nature of albitisation and potassic alterations, as self-evolved processes acting at grain-scale and large-scale external drivers may work together to account for the widespread distribution of successive sodic-potassic association at both micro- and macro-scales. Field evidence suggests that large-scale successive sodic and potassic alterations are commonly associated with externally driven changes in fluid chemistry and temperature18O-enriched water to monitor fluid-mineral exchanges17.The starting material for the experiments was a homogenous natural sanidine sample from Dellen Quarries, Niedermending, Mendig, Eifel, Rhineland-Palatinate, Germany. Some experiments were conducted in 18O was measured semi-quantitatively by nano-Secondary Ion Mass Spectrometry (nano-SIMS) and Raman spectroscopy. The nature of the reaction products was verified with Powder X-ray diffraction (pXRD), but Mineral Liberation Analysis (MLA) was used to quantify phase fractions, since pXRD was not able to distinguish the newly formed K-feldspar from the original sanidine. As the paper focusses on the change to the solid components during the hydrothermal alteration process, and not the solubility, fraction or speciation of feldspar minerals in fluid solutions51, the bulk fluid chemistry after experiments were not analysed. Analytical methods are described in detail in Supplementary Information.The products’ textures and compositions were characterised using Scanning Electron Microscopy (SEM) and Electron Micro Probe Analyser (EMPA), and the distribution of Supplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1


Texture analysis derived from Computed tomography (CT) might be able to better characterize fluid collections undergoing CT-guided percutaneous drainage treatment. The present study tested, whether texture analysis can reflect microbiology results in fluid collections suspicious for septic focus.Overall, 320 patients with 402 fluid collections were included into this retrospective study. All fluid collections underwent CT-guided drainage treatment and were microbiologically evaluated. Clinically, serologically parameters and conventional imaging findings as well as textures features were included into the analysis. A new CT score was calculated based upon imaging features alone. Established CT scores were used as a reference standard.The present score achieved a sensitivity of 0.78, a specificity of 0.69, area under curve (AUC 0.82). The present score and the score by Gnannt et al. (AUC 0.81) were both statistically better than the score by Radosa et al. (AUC 0.75). Several texture features were statistically significant between infected fluid collections and sterile fluid collections, but these features were not significantly better compared with conventional imaging findings.Texture analysis is not superior to conventional imaging findings for characterizing fluid collections. A novel score was calculated based upon imaging parameters alone with similar diagnostic accuracy compared to established scores using imaging and clinical features. Fluid collections are common and can represent ascites, seroma, hematoma, biloma, lymphocele, or abscess depending on the localization and underlying cause –4. The mThe important aspects to diagnose an infected fluid collection is clinical investigation, serological parameters, of most importance the inflammation parameter C-reactive protein (CRP) and lastly imaging modalities. CT is commonly performed in these patients to detect possible septic foci and to plan the following treatment.Some imaging features were reported indicative of an infection of a fluid collection, including air entrapment, rim contrast media enhancement and Hounsfield unit (HU) attenuation. However, these imaging features by itself cannot reliably exclude infection due to lack of a sufficient accuracy for correct diagnosis , 4.Those imaging and clinical features lead to a proposed score by Gnannt et al., which utilized CT features, clinical and serological parameters to predict the likelihood of infected abdominal fluid collections undergoing CT-guided drainage treatment in postsurgical patients . In thisTo this date, only one other study performed a validation analysis for this score and proposed a more accessible combination of imaging findings with only one clinical parameter, namely CRP to correctly diagnose infected fluid collections .This proposed simplified score achieved an even higher accuracy than the first one by Gnannt et al. with a reported sensitivity of 93% and a specificity of 80% .Texture analysis is a novel imaging analysis, which quantifies radiological images and can thereby provide imaging biomarkers –9. Most The principal hypothesis for this present work is that texture analysis might be able to reflect distinctive differences of fluid collections and might be a reliable tool to better characterize fluid collections and the need of drainage treatment. As a second part, the study performed a validation analysis for the two proposed scores to test the external validity and to validate, whether these scores can also be used in non-surgical patients and fluid collections of the pleura.The radiological database of a university hospital was retrospectively screened for patients treated with CT-guided percutaneous drainage between January 2017 and December 2020.Inclusion criteria were sufficient contrast enhanced CT for septic evaluation within 24 h before the intervention, sufficient native planning CT, available serological and microbiological evaluation. Overall, 738 patients were identified in the database, who were treated with a CT-guided percutaneous drainage. Several patients had to be excluded for the following reasons: n = 252 patients with no contrast enhanced CT within 48 h before drainage, n = 88 no microbiology, n = 56 with no sufficient clinical data for the score calculation, n = 18 no serological data, n = 4 CT texture analysis not possible due to artifacts.Finally, 320 patients  were included into the analysis. Figure At first, the CT images were qualitatively evaluated by one reader using the picture archiving and communication system . In unclear cases, a second reader with 5 years of experience in general radiology was consulted, and a consensus was met.The maximum length was measured.Hounsfield units (HU) measured with a region of interest (ROI) within the fluid collectionPresence or absence of a contrast enhancing rim of the fluid collection.Presence or absence of fat stranding surrounding the fluid collection.Presence or absence of entrapped gas within the collection.The quantitative evaluation of the CT images was performed accordingly to Gnannt et al. .The maxiThe electronic medical records system was utilized to extract the following clinical data: age, sex, underlying disease, presence of medication with immunosuppressive drugs (e.g. glucocorticoids or cytostatics), medication with antibiotics, body temperature and blood sample including CRP, white blood cell counts, procalcitonin and interleukin 6 within 6 h before percutaneous drainage.CT imaging was performed in a clinical setting with a 128 or 256 slices CT scanner . In all cases, 90 mL of iodinated intravenous contrast medium was given at a rate of 1.5 to 3.5 mL/s by a power injector , with a scan delay of 70 s after onset of injection for clinical evaluation of septic foci. Typical imaging parameters were 120 kVp, 150 to 300 mAs, and a slice thickness of 1 mm.The CT intervention was performed with a 16 slices scanner . In all patients, a native CT spiral scan was performed for planning of the intervention covering the body area of the known fluid collection. Typical imaging parameters were 120 kVp, 150 mAs, and a slice thickness of 2 mm.In all cases, a percutaneous drainage was placed within the fluid collection, size ranging from 8-F to 22-F depending on clinical presenting and localization.The previously proposed score by Gnannt et al. was calculated according to the publication . In shorThe second score by Radosa et al. was also calculated . This schttp://www.eletel.p.lodz.pl/mazda/) [One the next step, the texture analysis was performed blinded to the microbiological results. CT images further processed with the free available texture analysis software MaZda  , 11. Ima/mazda/) , 13. TheFigure All fluid collections were microbiologically analyzed during clinical work up blinded to the imaging results. As part of the CT-guided intervention, at least 5 ml of drained fluid was sent for microbiological analysis. According to current recommendations, fluid collections were considered infected if leukocytes and bacteria were detected on the Gram stain and/or the culture was positive for bacteria or fungi . If thesp values < 0.05 were taken to indicate statistical significance.Statistical analysis was performed using GraphPad Prism 5  and SPSS STATISTICS . Collected data were evaluated by means of descriptive statistics (absolute and relative frequencies). Spearman's correlation coefficient (r) was used to analyze associations between texture features and the proposed scores. Differences of the texture features between infected and non-infected fluid collections were investigated by two tailed Mann–Whitney test. Then, a Receiver operating characteristics (ROC) analysis was performed and compared between texture features and the scores. AUC characteristics between the scores were compared with DeLong test. A Random-Forest classifier as well as a multivariate analysis was used to construct a predictive model to classify infected fluid collections using qualitative as well as quantitative imaging parameters and serological parameters. In all instances, An overview of the descriptive statistics of the investigated demographic, serologic and imaging parameters is given by Table Overall, 402 fluid collections were investigated. In most patients one fluid collection was identified, in 68 cases 2 fluid collections were identified and in 7 cases 3 fluid collections were identified. There were 147 non-infected (36.7%) and 255 infected fluid collections (63.3%). In all patients, a successful percutaneous CT-guided drainage was placed within the fluid collection and the fluid was microbiologically evaluated.Table The resulting score was only defined by imaging parameters Table  in the mThe accuracy of the investigated scores is shown by Table Gnannt et al. achieved an AUC of 0.81 (95% CI 0.77–0.85), Radosa et al. an AUC of 0.75 (95% CI 0.70–0.79) and the present score an AUC of 0.82 (95% CI 0.78–0.86) Fig. a. The prp = 0.04), and not inferior to the score by Gnannt et al. (p = 0.23). The score by Gnannt et al. was significantly better than the score by Radosa et al. (p = 0.002). Figure The present score was significantly superior to the score by Radosa et al. (. p = 0.2. The scop < 0.001). The present score correlated both with Gnannt et al.  and the score by Radosa et al. .There was a strong positive correlation between the score by Gnannt et al. with the score by Radosa et al. , Radosa et al. an AUC of 0.71 (95% CI 0.65–0.77) and the present score an AUC of 0.80 (95% CI 0.74–0.85) Fig. b. The prOverall, 107 fluid collections were included into the analysis of pleural fluid collections.Again, the AUC values did not change significantly: Gnannt et al. achieved an AUC of 0.82 (95% CI 0.74–0.89), Radosa et al. an AUC of 0.77 (95% CI 0.68–0.85) and the present score an AUC of 0.82 (95% CI 0.73–0.89) (Fig. Table Several texture features were significantly different between infected and non-infected fluid collections. Table The present study elucidated whether CT scores can reliably predict infection of a fluid collection undergoing percutaneous CT drainage. A novel score was provided only utilizing CT findings, which was comparably good in regard of accuracy to the published scores. Another finding was that texture analysis derived from CT images does not provide additional value to diagnose infected fluid collections.Previously, several CT findings were identified to be indicative of infected fluid collection comprising increased attenuation, encapsulation with or without wall enhancement, presence of gas entrapment, and stranding of the surrounding tissue , 4, 6. HThat is why the previously proposed 2 CT scores are based upon a set of imaging features to achieve a better accuracy to diagnose infected fluid collections , 6. MoreOne rationale of the present study was that texture analysis could better characterize fluid collections due to its ability to quantify heterogeneities of radiological images .This has been extensively shown for oncologic imaging with papers elucidating the possible use of texture analysis to reflect histopathology and microstructure of tumors –9. HowevIt is widely acknowledged that higher attenuation of a fluid collection is mainly caused by debris , 6. HemoPresumably, debris and other associated findings of an abscess or infected fluid collection do not cause distinctive alterations of texture features in comparison to sterile hematomas and seromas, which can explain the negative results.Another part of the study was the validation of the two proposed CT scores by Gnannt et al. and Radosa et al. , 6. ThesContrary to the previous studies, the present study included pleural fluid collections suspicious for empyema and fluid collections in non-surgical patients into the analysis. This results in a larger patient spectrum but with the same important clinical question, whether a fluid collection is infected or not. Our results can therefore be considered as representative for all fluid collections, which are considered for CT-guided percutaneous drainage. To adjust for better comparability, the subanalyses were performed for postoperative abdominal fluid collections and pleural fluid collections separately. Nonetheless, both analyses showed similar results.The new proposed score only needs imaging criteria and was more accurate as the score by Radosa et al. and not statistically inferior as the more complex score by Gnannt et al. The new score could be used in clinical routine to guide treatment indication without any need of further anamnestic and/or serological information.CRP was discussed as the most important clinical parameter to diagnose infected fluid collection , 14. In It must be acknowledged that a superior CT based diagnosis of infected fluid collections can reduce possible drainage overtreatment. However, there are also non-infected fluid collections, which might need drainage treatment. For example, non-infected fluid collections with possible mass effect causing symptoms. Yet even for those cases, it could be useful for treatment planning to know the infection state of the fluid collection. For example, choice of drainage type could be influenced by this.There are several limitations of the present study to address. First, it is a retrospective study with possible known inherent bias. However, imaging and microbiology analyses were performed independently. Second, some serological inflammation parameters, including procalcitonin and Interleukin-6 were not available for all patients, which reflects clinical routine. Moreover, for every patient leucocyte count and CRP were available for analysis, which are most commonly used. Third, possible selection bias can be assumed as we only could include fluid collections undergoing CT-guided drainage treatment. There might be fluid collections not treated by this procedure due to low likelihood for infection or small size without possible drainage placement. Fourth, the imaging was analyzed by one reader. However, it was shown that an excellent interreader agreement can be assumed for the typical findings of infected fluid collections, which reduces possible bias , 16. TheAlbeit texture features derived from CT images were associated with the presence of infection of fluid collections, these were not superior to conventional imaging findings. A score was provided based upon imaging parameters alone, which was comparable to the published scores that are dependent on clinical and serological information. These findings could reduce the need for drainage therapy, which needs to be prospectively evaluated.


We conducted this study to evaluate the characteristics of the infectious fluid in soft tissue infection and investigate the utility of the biochemical tests and Gram stain smear of the infectious fluid in distinguishing necrotizing soft tissue infection (NSTI) from cellulitis.t test method and Fisher’s exact test were used to compare the difference between two groups. The receiver–operator characteristic (ROC) curves and area under the ROC curve (AUC) were used to evaluate the discriminating ability.This retrospective cohort study was conducted in a tertiary care hospital in Taiwan. From April 2019 to October 2020, patients who were clinically suspected of NSTI with infectious fluid accumulation along the deep fascia and received successful ultrasound-guided aspiration were enrolled. Based on the final discharge diagnosis, the patients were divided into NSTI group, which was supported by the surgical pathology report, or cellulitis group. The Total twenty-five patients were enrolled, with 13 patients in NSTI group and 12 patients in cellulitis group. The statistical analysis showed lactate in fluid (AUC = 0.937) and LDH in fluid (AUC = 0.929) had outstanding discrimination. The optimal cut-off value of fluid in lactate was 69.6 mg/dL with corresponding sensitivity of 100% and specificity of 76.9%. The optimal cut-off value of fluid in LDH was 566 U/L with corresponding sensitivity of 83.3% and a specificity of 92.3%. In addition, albumin in fluid (AUC = 0.821), TP in fluid (AUC = 0.878) and pH in fluid (AUC = 0.858) also had excellent diagnostic accuracy for NSTI. The Gram stain smear revealed 50% bacteria present in NSTI group and all the following infectious fluid culture showed bacteria growth.The analysis of infectious fluid along the deep fascia might provide high diagnostic accuracy to differentiate NSTI from cellulitis.The online version contains supplementary material available at 10.1186/s13017-022-00404-4. Necrotizing soft tissue infection (NSTI) is a life-threatening soft tissue infection which is characterized by rapid progressive destruction of the muscle fascia and the surrounding soft tissue , 2. A deThe fascia necrotizes and the tissue is damaged due to the rapid progressive infection from the subcutaneous tissue to the deep facia. Imaging studies have revealed obvious fat stranding and infectious fluid accumulation along the fascia layer , 8. HoweThis retrospective cohort study was conducted at the Chiayi Chang Gung Memorial Hospital, a tertiary care hospital in Taiwan, which has approximately 80,000 emergency department (ED) patients annually and 1300 hospital beds. This study was approved by the Institutional Review Board of Chiayi Chang Gung Memorial Hospital (No.: 201900447B0C601). Adult patients who presented to ED from April 2019 to October 2020 were enrolled based on the following three inclusion criteria: (1) severe soft tissue infection of the limbs with a clinical suspicion of NSTI by emergency medicine attending physicians, (2) infectious fluid accumulation along the deep fascia at the infection site revealed through point-of-care ultrasound (POCUS), and (3) successful ultrasound-assisted or ultrasound-guided aspiration of the infectious fluid. Patients with a history of operation, chronic osteomyelitis, and chronic or recurrent soft tissue infection  at the site of infection were excluded. Patients with skin lesions, such as tumor or deep trauma, and who previously received antibiotics were also excluded. Soft tissue infection with abscess formation such as cellulitis with pus formation and pyomyositis was excluded due to the clear diagnosis of pus-like infectious fluid.All clinical management decisions were made by the primary responsible ED attending physician. The standard management for patients with a clinical suspicion of NSTI presenting to the ED was the administration of broad-spectrum antibiotics and emergent orthopedic surgeon consultation for surgical intervention assessment. POCUS is a diagnostic adjunct that might help in the diagnosis of NSTI; NSTI is suspected if fluid accumulation is more than 2 mm deep along the fascia . UltrasoStaphylococcus aureus ). Statistical significance was considered when p value is < 0.05. Receiver–operator characteristic (ROC) curves were calculated to determine the biochemical variables’ optimal cutoff values of the biochemical variables for the diagnosis of NSTI and the area under the ROC curve (AUC) was used to assess the discrimination ability of each variable. In general, values of 0.5, 0.5–0.7, 0.7–0.8, 0.8–0.9, and > 0.9 for AUC suggest no, poor, acceptable, excellent and outstanding discriminations, respectively [All statistical analyses were performed using SPSS and R 3.6.0 software. The ectively , 14.p < 0.001), whereas white blood cell count, C-reactive protein (CRP), creatinine, blood urea nitrogen (BUN), serum lactate, length of hospital stay and length of intensive care unit (ICU) stay were higher (p < 0.05). The results are shown in the Table p = 0.03), as shown in Table Of the patients, 31 met the inclusion criteria , total protein (TP) (p < 0.001), lactate dehydrogenase (LDH) (p = 0.01) and albumin (p = 0.02) in the infectious fluid of the patients in the NSTI group as compared with that in the infectious fluid of the patients in the cellulitis group (Table p = 0.02) and pH (p = 0.01) of the fluid were revealed in the patients in the NSTI group.Statistical analysis showed a significant increase in the level of lactate p < 0.00, total pp = 0.16). One NSTI patient’s smear showed polymicrobial organisms with gram-positive cocci (GPC) and gram-negative bacilli (GNB). This patient’s infectious fluid culture revealed methicillin-susceptible S. aureus (MSSA), Klebsiella variicola and Proteus species.The comparison of Gram smear and fluid culture between the NSTI and cellulitis groups is shown in Table S. aureus (MRSA). Three NSTI patients’ smears showed monomicrobial organisms with GNB and the culture revealed three Vibrio vulnificus. Only one cellulitis patient’s Gram smear presented few bacteria , and the fluid culture showed no bacterial growth.Two NSTI patients’ smears showed monomicrobial organisms with GPC and the final fluid culture showed one MSSA and one Methicillin-resistant ROC analysis was performed on six infectious fluid parameters that had statistically significant differences between the two groups, and the optimal cutoff values were based on the Youden index (sensitivity + specificity − 1). The predictive ability of the infectious fluid to diagnose NSTI was assessed using AUC. The AUC of lactate in fluid and LDH in fluid showed outstanding discrimination for predicting the diagnosis of NSTI. The AUC of lactate in fluid was 0.937 and displayed a sensitivity and specificity of 100% and 76.9%, respectively, at the optimal cutoff value of 69.6 mg/dL. The AUC of LDH in fluid was 0.929 and displayed a sensitivity and specificity of 83.3% and 92.3% at the optimal cutoff value of 566 U/L. Furthermore, the AUC of albumin (AUC = 0.821), pH (AUC = 0.858) and TP (AUC = 0.878) in the fluid revealed excellent discrimination for differentiating NSTI from cellulitis. The results are shown in Additional file In this retrospective cohort study, we evaluated the characteristics of soft tissue infectious fluid above the deep fascia in comparison with the infectious fluid between NSTI patients and cellulitis patients were evaluated. In addition, the diagnostic ability of the infectious fluid to distinguish NSTI from cellulitis was evaluated. The result of current study showed that (1) LDH and lactate in the fluid had outstanding diagnostic accuracy for NSTI, (2) albumin, TP and pH of the fluid also had excellent diagnostic accuracy for NSTI, and (3) infectious fascial fluid’s cultures nay be a candidate to detect the bacterial pathogens in NSTI patients. To the best of our knowledge, this is the first study to analyze the characteristics of the infectious fascial fluid and evaluate its diagnostic ability. The infectious fluid’s laboratory tests and Gram stain smear are believed to be used as diagnostic adjuncts to help clinical physicians diagnose and manage NSTI NSTI is a serious infection of the deep soft tissue that causes rapid progressive destruction of the subcutaneous tissue and the deep fascia. Two distinct pathogenesis pathways have been described: 1) the evolution of NSTI with a defined portal of entry where the organisms enter the soft tissue causing local tissue infection, and (2) the evolution of NSTI without a defined portal of entry, which occurs with a nonpenetrating tissue injury  infected by transient bacteremia  the evol. During Although no previous study has investigated the diagnostic value of the soft tissue infectious fluid, these parameters have been used as diagnostic adjuncts in other body fluids,  to distinguish exudate from transudate –29. SeveVibrio vulnificus. Two patients in the NSTI group showed GPC in the fluid’s Gram stain smear. The following culture revealed S. aureus in either blood culture or fluid culture. Therefore, we found the Gram stain smear and infectious fascial fluid culture may be optimal tests for (1) providing diagnostic evidence of infective organisms spreading through the deep fascia and (2) obtaining the culture samples before empiric antibiotics.Early empirical antimicrobial therapy is one of the cornerstones of treatments for NSTI patients. The 2018 World Society of Emergency Surgery (WSES) and the Surgical Infection Society Europe (SIS-E) guidelines for the management of skin and soft-tissue infections suggested that the antibiotic treatment of NF should be aggressive (recommendation 1B), and incisional biopsy with Gram staining may be an important adjunct in early stages of suspected NSTI patients (recommendation 1C) . HoweverAlthough many risk indicators, laboratory parameters and diagnostic image examination, were investigated to differentiate between NSTI and cellulitis, recognizing NSTI is still challenging in the early stage of the infection , 30, 31.This study had three limitations that should be addressed. The first limitation was the small number of participants. It was because NSTI is a rare disease and the annual incidence of NSTI in Taiwan is about 3.26 hospitalizations per 100,000 persons/year . HoweverIn this retrospective cohort study, we found new timely diagnostic tests, using the infectious fluid along the fascia that might provide high diagnostic accuracy in distinguishing NSTI from cellulitis. Further research is required to validate of this study.Additional file 1: Fig. S1. Receiver operation characteristic (ROC) curves and the area under the ROC curve (AUC) demonstrating the diagnostic ability of laboratory data in infectious fascial fluid to predict the diagnosis of NF. The optimal cuff of value of each ROC curve was shown in the figure. (a) Albumin in fluid, (b) LDH in fluid, (c) glucose in fluid, (d) total protein in fluid, (e) lactate in fluid, and (f) pH of fluid.


Current guidelines on the management of patients with neovascular age-related macular degeneration (nAMD) lack clear recommendations on the interpretation of fluid as seen on optical coherence tomography (OCT) imaging and the incorporation of this information into an ongoing disease treatment strategy. Our objective was to review current guidelines and scientific evidence on the role of fluid as a biomarker in the management of nAMD, and develop a clinically oriented, practical algorithm for diagnosis and management based on a consensus of expert European retinal specialists. PubMed was searched for articles published since 2006 relating to the role of fluid in nAMD. A total of 654 publications were screened for relevance and 66 publications were included for review. Of these, 14 were treatment guidelines, consensus statements and systematic reviews or meta-analyses, in which OCT was consistently recommended as an important tool in the initial diagnosis and ongoing management of nAMD. However, few guidelines distinguished between types of fluid when providing recommendations. A total of 52 publications reported primary evidence from clinical trials, studies, and chart reviews. Observations from these were sometimes inconsistent, but trends were observed with regard to features reported as being predictive of visual outcomes. Based on these findings, diagnostic recommendations and a treatment algorithm based on a treat-and-extend (T&E) regimen were developed. These provide guidance on the diagnosis of nAMD as well as a simple treatment pathway based on the T&E regimen, with treatment decisions made according to the observations of fluid as a critical biomarker for disease activity. Since the widespread introduction of optical coherence tomography (OCT) for the visualisation of the back of the eye in patients with eye diseases such as neovascular age-related macular degeneration (nAMD), the evaluation of lesion morphology using OCT has become a key part of the clinical decision-making pathway . MarkersRecent advances in OCT technology have led to increases in speed and resolution that permit the detection of small structural changes to the retinal layers . HoweverThe objective of this consensus article is to review the current guidelines and scientific evidence on the role of fluid as a biomarker in the management of nAMD and provide clinically useful recommendations based on a consensus of expert European retinal specialists. Furthermore, limitations of current literature and areas of further research are also highlighted.A preliminary review of the literature on the role of fluid in the management of nAMD was performed by Novartis in preparation for a roundtable discussion with European retinal specialists , held in Zurich, Switzerland (19 July 2019). During this initial meeting, the available scientific evidence—and the lack of it—were discussed, resulting in the proposal from the consensus panel to develop simplified treatment recommendations in nAMD. The literature review was subsequently repeated with revised search parameters and the updated results were subject to further review by the consensus panel during the development of the treatment recommendations, ensuring scientific rigour and unbiased interpretation. Novartis was not involved in the interpretation of the literature search results or the development of the treatment recommendations.The repeated literature search of PubMed was performed according to the predefined search parameters shown in Table The evidence was discussed by the consensus panel and used, along with their expert opinion and experience, to inform the development of a consensus management algorithm for patients with nAMD based primarily on observations of fluid from OCT monitoring. The nAMD-specific terminology used within this article follows recent consensus nomenclature for reporting nAMD data . The terThe literature review was performed on September 25, 2019  guidance on the use of ranibizumab in nAMD from 2009, new subretinal fluid (SRF) with or without haemorrhage is included as one criteria for treatment initiation, while their definition of disease activity for continuation of treatment includes IRF, SRF, sub-RPE fluid and haemorrhage . In lateFew guidelines distinguished between types of fluid when providing recommendations, with the same retreatment approach generally recommended regardless of the type and location of fluid observed. One of the few that made a distinction between fluid types was the 2014 EURETINA guideline on nAMD, which advised that IRF, SRF and RPE detachments are important signs of neovascular activity independent of central retinal thickness (CRT), and that a ‘zero tolerance’ approach to OCT criteria is justified given the rapid progression of exudative features and progressive loss of vision when initiation of treatment is delayed in nAMD. However, longstanding persistent IRF should be considered a sign of irreversible retinal damage which should not prompt continued retreatment. Performing OCT was recommended as the most useful tool for evaluating morphological changes since it provides the most accurate reflection of the recurrence of disease activity. Qualitative morphology-based OCT data were considered to be more sensitive than current quantitative measurements such as CRT for detecting choroidal neovascularisation (now termed macular neovascularisation [MNV]) activity .In the American Academy of Ophthalmology preferred practice pattern for AMD from 2015, there is no specific mention of how to interpret retinal fluid in diagnosis or follow-up, other than a statement that as-needed treatment should be based on the presence or absence of SRF or IRF . FinallyA number of expert consensus statements have provided guidance on the management of nAMD including recommendations relating to fluid and other anatomical parameters visualised using OCT. These are broadly consistent but differ in the detail of interpreting the various morphological features.In 2011, a group of 22 European experts provided consensus recommendations for anti-vascular endothelial growth factor (VEGF) management of nAMD based on morphological criteria. Suggested retreatment criteria under a pro-re-nata (PRN) regimen included IRF, SRF, diffuse foveal thickening and expanding serous pigment epithelium detachment (PED). Criteria for delaying treatment included the absence of the above criteria, stable serous PED and stable IRF that has not responded to three intravitreal injections .In a 2017 expert round-table consensus on the treatment of nAMD with aflibercept in the second year of therapy, fluid was a recommended consideration when making the decision to maintain a fixed regimen or move to a treat-and-extend (T&E) dosing schedule. The criteria for not extending the treatment interval included persistent macular fluid with stable vision, recurrent fluid, and decrease in vision in the presence of fluid. Extension of intervals between treatments was recommended for eyes with no macular fluid and stable vision .A recent Greek consensus statement on the management of nAMD recognised the importance of morphological signs of disease activity observed using OCT, which the authors note correspond to early signs of recurrence prior to measurable loss of VA. The main anatomic parameters to be taken into consideration according to their recommendations were CRT, SRF, IRF, anatomy of the outer retinal layers and PED .Four systematic reviews were included in the literature review. The earliest of these was a systematic review on OCT for diagnosis, monitoring and guiding treatment for nAMD by Mowatt and colleagues from 2014, which concluded that strategies involving OCT alone for diagnosis and/or monitoring were unlikely to be cost-effective, while those that also included fluorescein angiography (FA) and other imaging techniques were more likely to be considered cost-effective. However, many of the studies included in this review used older, time-domain OCT technology which may have compromised the specificity of the technique in terms of detecting active nAMD. For the purposes of this review, nAMD was considered to be active or inactive, with no specific discussion relating to fluid . In contA systematic review of the evidence on using morphological predictors to modify treatment protocols in nAMD was performed by Ashraf et al. , findingThe 52 primary publications of clinical trials and studies retrieved by the literature search were reviewed for relevant detail on the role or impact of fluid in nAMD. Of these, one publication was the primary output of a randomised controlled trial (RCT) , 21 publSeveral studies reported that the presence of baseline SRF predicts a good response to anti-VEGF treatment, resulting in favourable visual outcomes , 40–42. Several publications found the type or spatial localisation of fluid to have limited prognostic value in terms of predicting response to anti-VEGF therapy , 54, 55.A significant number of studies found either abnormally thick or abnormally thin retinas to be associated with poor outcomes , 56, 57.Finally, a small number of publications commented on correlations between fluid and required anti-VEGF injection frequency. Two publications reported that a thicker retina at baseline was associated with greater injection requirements , 60, whiBased on the available scientific evidence described above and the experience of the consensus panel, an algorithm for the most optimal management of patients with nAMD based on fluid observed using OCT and other imaging technologies is recommended, irrespective of country guidance and resource constraints, as shown in Fig.  that specifically aimed to evaluate the impact of fluid in the management of nAMD . Even thThe imaging technologies used in the studies included here have not remained constant over the time span of the literature review. OCT has evolved from time domain to spectral domain modalities, meaning that the observations reported by the earliest publications returned by the literature search are not directly comparable to the more recent publications. Several of the larger RCTs used these older imaging techniques, which may detract from the relevance of their findings to current practice. Other measured parameters may have also changed over time.A final limitation of this work is that for the purposes of providing clear guidance that can be used on a day-to-day basis by the practising clinician, this review and consensus focusses only on the role of fluid in nAMD. In addition to fluid, a range of other morphological features visible on OCT such as external limiting membrane, ellipsoid zone and RPE disruption, and the presence of PED and hyperreflective material have been associated with poor visual acuity outcomes , 71–75. In conclusion, gaps exist in the scientific literature on the role of fluid in the management of patients with nAMD. The limitations described here highlight the real need for appropriately designed and executed studies to provide a standardised and detailed understanding of the appearance of different specific fluid manifestations and their consequences on clinical outcomes. However, it is quite clear that the primary treatment goal is to eliminate fluid as effectively as possible. Future research into this important area could provide valuable insights to direct optimal treatment to achieve this. In the meantime, following expert consideration of the evidence available, we recommend that patients with nAMD receive anti-VEGF therapy according to a T&E regimen with treatment intervals determined according to fluid-based disease activity parameters observed using OCT.


Dear Editor,2O2) is widely used as a signaling molecule in plants during development, wounding, pathogen or symbiotic interaction, and a wide range of abiotic stresses  in combination with light  render the sensor more responsive due to the diminished reducing power , we generated stable HyPer7 reporter lines. These plants did not show any obvious phenotype (l-buthionine sulfoximine (BSO)  and compared its response with reporter lines expressing roGFP2-Orp1 and HyPer   caused one (BSO)  was unrene (BSO)  was fullne (BSO) . This suin yeast . With GSnd HyPer . When peerfusion . The speh HyPer7 . Subsequd probes , but didd probes . This sud probes .2O2 in roots consistently showed a more pronounced response of HyPer7 (2O2 in leaves, the same H2O2 concentration did not cause a ratio increase in roots, or even caused a complete lack of excitability at 488 nm preventing any ratiometric analysis. A pronounced drop in the fluorescence ratio of cpYFP with H2O2 identifies the decrease of the HyPer ratio to be caused by H2O2-induced acidosis in the cytosol (Direct comparison of HyPer and HyPer7 for their response to externally added Hf HyPer7 . While H cytosol . pH-clam cytosol . This pH2O2 in live plant cells, we tested the response to oxidative stress generated at the photosynthetic electron transport chain. In leaves, 50 µM MV in combination with light causes the formation of H2O2, which is detectable with roGFP2-based probes (To explore the capability of HyPer7 for sensing stress-induced Hd probes . The resd probes . Continud probes . While Hd probes . The res2O2 release from chloroplasts, and that these low amounts of H2O2 can be detected by HyPer7. Laser-induced oxidation of HyPer declined within minutes indicated by a decreasing fluorescence ratio (In pavement cells of cotyledons, illumination by laser light during scanning already caused a gradual oxidation of HyPer7, which increased depending on the zoom factor . Surprisce ratio . The cap2O2 than current probes. Nonetheless, the Arabidopsis cytosol appears to lack an efficient reduction system for HyPer7, which may limit its use for fast dynamic studies. With increased sensitivity, HyPer7 offers the possibility of detecting physiological H2O2 fluxes and thus opens the door for further studies on intracellular H2O2 signaling during normal development and under environmental stress. At the same time the high sensitivity, at least in green tissues, bears the risk of generating artifacts if non-photosynthesis-related H2O2 signaling processes are to be investigated. Knowing these potential artifacts should help designing appropriate control experiments and with that generate data that help elucidate H2O2 signaling.In summary, HyPer7 is largely pH-insensitive and more sensitive to HThe following materials are available in the online version of this article. Expression of the HyPer7 sensor in Arabidopsis. Effect of GSH depletion on the oxidation of genetically encoded H2O2 probes. Excitation spectra of HyPer7 in vivo and in vitro. Determination of minimum and maximum oxidation of different H2O2 probes. Hydrogen peroxide causes acidification in the cytosol. Response of HyPer and HyPer7 to changes in intracellular pH. MV-induced photo-oxidative stress and the elicitor flg22 cause oxidation of H2O2 probes in the cytosol. Oxidation of HyPer7 depends on laser light intensity reaching the scanned area. Methodology used in this study.kiab306_Supplementary_DataClick here for additional data file.


Emerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling successful tumour control in all treated mice. Targeting Tregs by blocking the leukocyte-enriched PI3Kδ is an attractive target for therapy given that, compared with conventional T cells, Tregs are substantially more dependent on PI3Kδ activity, with PI3Kδ inhibition dampening their proliferation and suppressive functions.6Immunotherapies that unleash powerful anti-tumour T cell responses, such as anti-PD1/PD-L1 or anti-CTLA4 therapy can have impressive clinical benefit, albeit only in a small proportion of patients. These therapies aim to improve the potency of the anti-tumour response and/or to increase the frequency of tumour-infiltrating CD46 Using this PI3Kδ inhibitor, we demonstrated that while all treated animals exhibited some level of tumour control, these mice fell into two groups namely those that showed only slowed tumour growth, which we refer to as non-regressors (PI-3065 NR), and those that showed significantly reduced tumour burden .7 Investigating the differences between these two groups, we found that complete control of tumour burden was reliant on: (i) the dampening of a Treg response and (ii) the generation of an improved antigen-specific CD8 response.Using genetically engineered mice with systemic or Treg-selective PI3Kδ inactivation, Ali and colleagues previously demonstrated increased resistance to tumour growth, while pharmacological inactivation using the PI-3065 PI3Kδ inhibitor provided partial tumour control in treated animals.7 .Several PI3Kδ inhibitors are now progressing in clinical trials to determine their potential utility as an immunotherapy for solid malignancies. Recent data have also rekindled the early observation that, in addition to its high constitutive expression in leukocytes, PI3Kδ can also become highly expressed in some solid tumour cell types, such as breast and melanoma.PI3Kδ inhibitors in clinical trials include AMG-319 as a monotherapy in a window-trial in head and neck cancer  or in combination with anti-PD1 immune checkpoint therapy in a range of advanced solid tumour indications , with iOnctura testing their PI3Kδ inhibitor IOA-244 as monotherapy and in combination with the chemotherapeutics pemetrexed/cisplatin in a range of advanced solid tumour indications (NCT04328844). Elucidating the effect of PI3Kδ inhibition on the immune response within each tumour type, specifically the anti-tumour CD8 and Treg response, will be key in determining which tumours are likely to be responsive to PI3Kδ inhibition. In those tumours that are responsive, detailed phenotyping of the tumour-infiltrating lymphocytes has the potential to highlight which co-inhibitory receptors should be targeted with additional immune checkpoint blockade to improve the clinical response.


Correction to: BMC Geriatr 21, 243 (2021)https://doi.org/10.1186/s12877-021-02186-xbold. The original article has been updated.In the original publication  there waIncorrect fundingThis research was supported by the Health Department grant number (SLT008/18/00011) from the Generalitat of Catalunya (Spain) and by a grant from the Territorial Management of Barcelona of the Institut Català de la Salut  to the first author (JJZS) in the 2018 edition. The funders had no role in review design, decision to publish, or preparation of this manuscript.Correct fundingThis research was supported by, the Health Department grant number (SLT008/18/00011) from the Generalitat of Catalunya (Spain), by a grant from the Territorial Management of Barcelona of the Institut Català de la Salut  to the first author (JJZS) in the 2018 edition, and by the MUTUAMCONVIURE Foundation's Research Award in Social and Health Care (18th Edition). The funders had no role in review design, decision to publish, or preparation of this manuscript.


Frontiers in Psychiatry 2020 Dec 23; 11:595584)(Appeared originally in


Due to a production error, the funding numbers for each funder were erroneously omitted. The corrected Funding section appears below.We would like to thank all the authors and the financial support by the National Key Research and Development Program of China (grant no. 2019YFD1101202), Jiangsu Province Natural Science Foundation for Young Scholars (grant no. SBK2021040275), Natural Science Foundation for Distinguished Young Scholars (grant no. SBK20190035), Program of National Natural Science Foundation of China , Key Research and Development Plan of Jiangsu Province (grant no. BE2020712 and BE2019001), Six Talent Peaks Project in Jiangsu Province (SWYY-045), and High-Level Innovation and Entrepreneurship Talents Introduction Program of Jiangsu Province.The publisher apologizes for this mistake. The original version of this article has been updated.


In semiarid areas, low productivity of crops has been attributed to lack of appropriate soil moisture conservation practices since droughts and soil erosion are rampant in most areas of this region. Consequently, ridge-furrow rainwater harvesting is widely used in these regions across the globe. Despite ridge-furrow being widely practiced, tied-ridge-furrow has not been extensively adopted by small-scale farmers in semi-arid regions. Consequently, the effectiveness of tied-ridge-furrow as a viable method of increasing crop yield has received less attention.Sorghum bicolor) and pearl millet (Pennisetum glaucum) grain yields.For large-scale implementation, a detailed assessment of how ridge furrow, tied–ridge-furrow with fertilizer, tied-ridge-furrow with mulching and tied-ridge-furrow without mulching or fertilizer influence crop yield in different agro-environments under varying climatic conditions is needed. This study used the PRISMA guidelines to determine the impact of tied-ridge-furrow rainwater harvesting technique with mulching or fertilizer on sorghum (−1). Grain yield of millet significantly increased by 20–40% in Africa from 18 study observations in tied-ridge-furrow with fertilizer application as compared to tied-ridge-furrow without mulching or fertilizer treatments. This might be due to the significant increase in total nitrogen by 13–42% in the soil at <50 mg kg−1 quantity which had an effect size of 469.14 . In terms of soil texture, grain yield of millet and sorghum significantly increased in heavy textured soils  with an effect size of 469.14  compared to light and medium-textured soils of zero effect sizes. Millet and sorghum grain yields in tied-ridge-furrow with mulching, on the other hand, were not significantly different from those in flat planting. This may be due to the mulching materials used in those tests.Sorghum grain yield increased by 17% greater in tied-ridge-furrow without mulching or fertilizer in comparison to flat planting. This may be due to increase in soil organic carbon in the region (9 g kgIn view of yields of sorghum and millet increased significantly by 32% and 17% in tied-ridge-furrow without mulching or fertilizer treatment compared to flat planting and tied-ridge-furrow with fertilizer treatment compared with tied-ridge-furrow without mulching or fertilizer treatment, respectively, this study recommend the use of fertilizers in a tied-ridge-furrow system to increase grain yield in semiarid areas compared to flat planting. Again, the study recommends more research on tied-ridge-furrow systems with other organic mulches and fertilizers in semiarid areas. Globally, droughts characterized by low soil water availability and poor soil fertility are major factors limiting plant growth and yield . The proIn rain-fed agriculture, the RFRWH method has been beneficial and widely adopted by local farmers to increase crop water use efficiency . The furBesides drought, another factor constraining productivity in rain-fed agriculture is low soil fertility . The maie.g., trying to compare the incomparable)  recognizing overviews from a range of separate and disparate studies, and (b) determining inadequacies in existing research such that new preferences for future research can be proposed . Meta-anparable) . As new parable) .Although some field experiments have been conducted to assess the impact of fertilizer, yield and mulching use relationship in ridge-furrow rainwater harvesting system, no comprehensive, and quantitative analyses of available published data have been conducted thus far. Therefore, investigating grain yield across semiarid regions of Asia and Africa under the influence of tied-ridge-furrow with inorganic fertilizer is one of great importance to sustaining rain-fed agriculture on the Loess Plateau. Through a synthesis of existing results, the current study examined the impacts of tied-ridge-furrow with inorganic fertilizer on grain yield. The objectives of this study were (1) to quantify the responses of grain yield to fertilizer and mulching and establish the yield-fertilizer or mulching use relationship on the Loess Plateau and (2) to compare the effects of different tied-ridge-furrow systems with or without fertilizer and mulching methods on yield. To achieve these objectives, the PRISMA guideline  was usedPeer-reviewed papers published in English between 2000 and 2020 that investigated the effects of tied-ridge-furrow with or without mulching or fertilizer on field crops were retrieved from online databases , JSTOR, and Science Direct) as previously described in The literature search for the meta-analysis (MA) was done using the following keywords: ‘rainwater harvesting’, and/or ‘ridge furrow’, and/or ‘tied ridge’, and/or ‘mulching’ and/or ‘yield’. The search yielded 101 publications, which were screened based on the following inclusion criteria: (1) on-field experimentation with at least ridge-furrow, tied-ridge-furrow, mulched ridges, fertilizer, flat planting, and no mulch treatments; (2) experimental fields recorded were located in rain-fed semiarid agricultural areas, and (3) crop yield was reported.Based on the inclusion criteria, 85 of the papers found were excluded from this meta-analysis. As such, 16 papers were subjected to the study . The pubPennisetum glaucum) and sorghum (Sorghum bicolor) in different ridge-furrow rainwater harvesting practices with or without mulching and fertilizer, while Heterogeneities may have occurred from the following factors: (1) the researchers had different preferences and personal experiences; (2) many of the field experiments did not include any long-term observations; (3) the experimental fields exhibited different yield statuses, mulching and fertilizer application rates before sowing; and 4) field management practices and climatic conditions differed during crop-growing seasons. Although the effect of tied-ridge-furrow with fertilizer and mulching can be evaluated through meta-analytical method, underlying sources of meta-analytical uncertainties require further research.  field maThe importance of publications examined in this analysis was determined using the Newcastle Ottawa Scale (NOS) . A 7-poiWe used construction confidence interval analysis to correlate the severity of the response ratio between the ridge-furrow, tied-ridge-furrow, and flat planting treatments . Accordit and θc are mean values of yield in tied-ridge-furrow and flat planting, respectively. According to where θwhere a negative percentage change indicates a decrease in tied-ridge-furrow variable when compared to flat planting, and a positive percentage change indicates an increase in the corresponding variable when compared to flat planting. Subsequently, in addition to the means, sample sizes of the variables and standard deviation (SD) were extracted from the papers or estimated using the equation :For studies that did not record SD, average coefficient of variation (CV) within each data set was calculated, and the unavailable SD was approximated using the following equation :2 and I2 statistics , a random-effects model was used. The ridge-furrow, tied-ridge-furrow with fertilizer, tied-ridge-furrow with mulching, and flat planting groups’ mean differences were weighted according to their SE and sample sizes, and their confidence intervals (CI) were calculated from their weighted effect sizes. When there was no zero in the 95% CIs of the effect size of treatment, the impact of that treatment was significant. Concurrently, when the 95% CIs contain zero, the treatment was not significant. To demonstrate distribution symmetries of individual experiments, frequency distribution of effect sizes (Odds ratio) was calculated using an Excel 2010 spreadsheet.where θ is average of flat or tied-ridge-furrow planting with mulch or fertilizer. Since effect sizes of tied-ridge-furrow with mulching or fertilizer and flat planting for crop yield are continuous variables, random-effects models were implemented using the Nordic Cochrane Centre’s Review Manager Program . The heterogeneity between studies was assessed in this analysis using Chiatistics . The I2 ogeneity  , loamy sand and loam soils (medium), and clay loam, silty clay and clay soils (heavy). Data from most studies analyzed were in tables thus were transferred into the database of this MA directly.Literature search yielded 101 publications (papers), which were screened based on inclusion and exclusion criteria and 16 papers were subjected to the study. China was the only Asian country examined in this study. African countries considered in this study were Ethiopia and Nigeria. This MA focused on the influence of tied-ridge-furrow as a viable method for increasing crop yield. The studies considered in this MA examined sorghum and millet production in Asia and Africa under temperatures > 20 °C, precipitation > 500 mm, soil organic matter < 10, pH > 6 to 7, soil organic carbon < 9 g kg−11. However, most soils are low in fertility mainly due to nutrient mining as about K (27.3 kg ha−1), P (5.9 kg ha−1), and N (22.5 kg ha−1) per annum are lost from pearl millet production. In Nigeria, rainfall unpredictability and recent variations in weather conditions threatens crop yield and farmers income. Since this condition is not different from Ethiopia, a drought tolerant and high yielding sorghum variety, PAN 8625 is widely grown, with an average yield of 5,533.83 kg ha−1. This MA showed that tied-ridge-furrow with mulching is mainly practiced in Africa (Ethiopia and Nigeria) where temperatures are mostly greater than 20 °C (p = 0.48). Since mulches have a major impact on soils they are applied to, the absence of a significant difference is most likely attributable to the mulching materials used in those tests. The mulching materials used in these studies were guinea grass (Panicum maximum) which was applied on the ridges at 21,600 kg ha−1 and 0.2 m thick and covered with 75% of soil after crop propagation and grass mulch applied at 10 cm thickness.Through a synthesis of existing results, the current study examined impacts of tied-ridge-furrow with inorganic fertilizer on grain yield. Literature search yielded 101 publications (papers), which were screened based on inclusion and exclusion criteria and 16 papers were subjected to the study. China was the only Asian country examined in this study. African countries considered in this study were Ethiopia and Nigeria. In Ethiopia, sorghum is produced in almost all areas occupying an estimated cumulative land area of 1.68 million ha with national average yield of 2,369 kg haan 20 °C . Results−1) has increased significantly (p < 0.0001) in this region. The I2 test for sorghum yield in this MA yielded a value of 5%, which was less than 25%, suggesting that the studies used in this analysis were not heterogeneous. The random-effects model was therefore used because Chi2p-value was < 0.05. However, concerning precipitation, temperature, pH, total nitrogen, phosphorus, soil texture, and soil organic matter, there was no significant difference (p > 0.05) in crop yield in these regions.When compared to flat planting, increase in sorghum yield in tied-ridge-furrow without mulching or fertilizer fields was significant. In 14 study observations, tied-ridge-furrow with no fertilizer or mulching applied treatment yielded 17% sorghum grains greater than flat planting. Sorghum yield had an effect size of 1,197.92  with a p-value of 0.05 . This map = 0.03) was 469.87 . The I2 for this comparison is 0%, indicating that there is no heterogeneity among the studies included in this study. This might be due to the significant increase in total nitrogen (13–42%) in the soil at < 50 mg kg−1 quantity which had an effect size of 469.14 . With an effect size of 469.14 , yields in soils with heavy texture  also increased significantly. This subgroup also had 0% in I2 test, which may have affected the substantial increase in soil organic matter in the area. In this MA, effect size of soil organic matter was 469.87 . However, concerning precipitation, temperature, pH, total nitrogen, and phosphorus, there was no significant difference in crop yield in these regions.The yield of millet increased 20–40% in Africa (Ethiopia and Nigeria) from 18 study observations in tied-ridge-furrow with fertilizer application as compared to tied-ridge-furrow without mulching or fertilizer treatments . The effThe current study examined impacts of tied-ridge-furrow with inorganic fertilizer and mulching on grain yield through a synthesis of 16 existing publication results. In this MA, crop yield had no significant difference between tied-ridge-furrow with mulching and flat planting Refer to , which iVigna Unguiculata L.) yield and yield components were not significantly affected by moisture conservation practices in their experimental study, yield advantage of tied-ridge-furrow was 26% compared to flat planting. The grain yield of pearl millet (Pennisetum glaucum) obtained from tied-ridge-furrow  was higher by 12.52% compared to farmers’ practice  (−1 during seasons with moderate intensity storms. Similar research by p < 0.05) difference in yields of about 3,000 kg ha−1 compared to flat planting whose yields were about 1,500 kg ha−1  . In contkg ha−1) . This is kg ha−1 . In anotplanting .−1) for pearl millet, with application of micro-dose fertilizer with dry seed in tied-ridge-furrow and recommended fertilizer rate with dry seed in tied-ridge-furrow, respectively. In similar research, −1 (34.5%) due to tied-ridge-furrow compared with flat planting on Entisols with NP followed by 1,255 kg ha−1 (48.5%) on Alemaya black clay soils (Vertisols) under fertilized conditions, indicating that yield response to water conservation treatments was higher under fertilized than under unfertilized conditions on the two soils. Accordingly, maximum sorghum grain yield  under fertilized and  unfertilized conditions were obtained from closed tied-ridge-furrow with planting in-furrow (-1) recorded was with the application of micro-dose fertilizer with primed seed in tied ridge with intercropping mung bean and recommended fertilizer rate with dry seed in tied-ridge-furrow (Conversely, n-furrow . In addie-furrow . This, ae-furrow . This lee-furrow . Therefoe-furrow .Given the poor soil fertility level of semiarid areas in Asia and Africa, a single intervention through rainwater harvesting techniques may not bring a substantial impact on crop productivity. Based on the results of this study, it can be concluded that tied-ridge-furrow rainwater harvesting system with fertilizer application retains soil moisture and could be adopted by farmers in semiarid areas to increase crop yields. While there was no substantial difference in crop yield in tied-ridge-furrow with mulching treatment compared to flat planting, there was a significant increase in sorghum yield in tied-ridge-furrow without mulching or fertilizer fields compared to flat planting. In view of yields of sorghum and millet increased significantly in tied-ridge-furrow without mulching or fertilizer treatment compared to flat planting and tied-ridge-furrow with fertilizer treatment compared with tied-ridge-furrow without mulching or fertilizer treatment, respectively, this study recommend the use of fertilizers with tied-ridge-furrow system to increase yield in semiarid areas compared to flat planting. The study recommends more research on tied-ridge-furrow systems with other organic mulches and fertilizers in semiarid areas.10.7717/peerj.11904/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.11904/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.11904/supp-3Supplemental Information 3Click here for additional data file.


Patients with malignant pleural mesothelioma (MPM) or pleural metastases often present with malignant pleural effusion (MPE). This study aimed to analyze the effect of pleural fluid on cancer cells.Established patient-derived cancer cell cultures derived from MPE  were seeded in 100% pleural fluid  and proliferation was monitored. In addition, the establishment of new MPM cell cultures, derived from MPE specimens, was attempted by seeding the cells in 100% MPE fluid.All established cancer cell cultures proliferated with similar growth rates in the different types of pleural fluid. Primary MPM cell culture success was similar with MPE fluid as with full culture medium.in vitro, regardless of the source of pleural fluid. These results support the hypothesis that pleural fluid has important pro-growth biological properties, but the mechanisms for this effect are unclear and likely not malignant effusion specific.Pleural fluid alone is adequate for cancer cell proliferation  Malignant pleural effusion (MPE) is a common complication which affects patients with pleural metastases, or malignant pleural mesothelioma (MPM) , 2. The MPE is a protein-rich fluid including growth factors and cytokines, with pro-inflammatory, oncogenic and angiogenic properties such as vascular endothelial growth factor (VEGF) , 11, andin vitro had increased cell viability compared to cells exposed to serum-free and serum-enriched medium. In addition, MPM cell death was significantly less likely after exposure to cisplatin/pemetrexed combination in the presence of 30% MPM MPE fluid, than cells that were only exposed to the chemotherapy .Laboratory data support this view - Cheah et al. reported that MPM cells exposed to 30% MPM MPE fluid otherapy . Althougin vitro and in vivo settings, potentially providing a closer representative of cancer cells in vivo which are bathed in pleural fluid. This study aimed to analyze whether pleural fluid alone is adequate for cancer cell proliferation in vitro.Patient-derived cancer cell cultures are a faithful laboratory model with the potency to recapitulate the biology of the disease –15. PatiPleural fluid samples were collected from patients who gave consent for inclusion in the Oxford Radcliffe Pleural Biobank . This project was approved by the Oxford Radcliffe Biobank Central University Research Ethics Committee (CUREC) number: 19/A107. Pleural Biobank is a prospective collection of clinical specimens derived from patients presenting with pleural effusion of varied diagnoses.°C for up to 3 days) was used, but when this was not available, freshly-thawed-from-frozen unfiltered pleural fluid samples were used.Pleural fluid (50ml) was collected from patients with MPM who underwent pleural procedures as part of their standard medical care. The fluid was collected in sterile 50ml conical centrifuge tubes and processed for cell culture within 2-3 hours of sampling. The protocol used for cancer cell culture is described elsewhere . When plThe cells from established patient-derived MPM cell culture  were seeded at 100,000 cells per well in a 6-well plate, in 2ml of MPM MPE pleural fluid.°C and 5% CO2.The cells were incubated at 37Serial live images of the cells within the well were taken daily to monitor growth and proliferation.The pleural fluid was refreshed every 48 hours.®, D5671] for 12 hours before starvation medium was changed to 100μl of exudative MPM MPE fluid  or transudate MPE fluid (metastatic lung adenocarcinoma MPE (cytology positive for adenocarcinoma) with total fluid protein 8 g/l, glucose 5.7 mmol/l, LDH 190 IntUnit/l). There were at least 6 replicates for each cell culture at each time point. The pleural fluid was refreshed every 24 hours. Cell viability was assessed at 4, 8, 12, 24 and 48 hours using CellTiter-Glo®. A well-characterized, commercially available biphasic MPM cell line CRL-2081(MSTO-211H)™ (derived from human MPE fluid) was purchased from ATCC® and used as a control.MPM cells from established patient-derived MPM cell cultures , breast cancer (BRST-156) and lung adenocarcinoma (LNG-183) cell cultures, and with exudate and transudate MPE fluid, as well as non-MPE pleural fluid from a patient with heart failure-related pleural effusion  (minimum of 3 replicates per cell culture). Cells were incubated in an IncucyteUsing Fiji (ImageJ)  version in vitro  as per standard method used in our laboratory for primary cell culture, and in parallel, half the cells from the same MPE fluid sample were seeded in matched MPE fluid from the same patient instead of in full medium. The associated pleural fluid cytology result as reported by the clinical histopathologist as part of the patient’s routine clinical care was collected from the medical records. The method used was as follows:Pleural fluid samples from patients diagnosed with MPM were centrifuged at 800G for 10 minutes and the supernatant was aspirated and saved for later use.®) and cells were kept at room temperature for 5 minutes.The sedimented cells were resuspended in 3-5ml of red blood cell lysis solution (Qiagen® MFCD00121855).The sample was then centrifuged again at 500G for 5 minutes. The supernatant was aspirated and discarded, and the pelleted cells washed with phosphate buffered saline (Sigma-Aldrich2.The sample was centrifuged one last time at 500G for 5 minutes. The pelleted cells were resuspended in 1ml of the MPE fluid saved from step 1 (or in 1ml full medium for the control), and then transferred to a cell culture treated plate with a further 9ml MPE fluid (or in 9ml full medium for the control) in it, and incubated at 37°C and 5% COThe MPE fluid (or full medium for the control) was refreshed every 48 hours, and the plates were monitored regularly under a light microscope.The cells were allowed proliferate until >90% confluence. The cells were then split, and about 70% of the cells were transferred to a new culture dish this time in full medium.The serial live images of the cells within the wells were taken using ZEISS Axiocam 506 mono, to monitor growth and proliferation. The percentage confluence was calculated from the images using Fiji (ImageJ)  version Kruskal-Wallis test was used to compare mean size of cells seeded in the different pleural fluid types. GraphPad PRISM version 8.3.0  was used for the growth curves and the statistics.in vitro, obtaining nutrients solely from pleural fluid. Results revealed that the cells show increased levels of confluency with time , MESO-174 (biphasic), MESO-024 (biphasic), MESO-027 (epithelioid)] to compare exudate and transudate MPE fluid, and transudate non-MPE pleural fluid  as a control. In 3 , cell culture was successful in both MPE fluid and cell culture medium, in 1/6 (16.7%) cell culture was unsuccessful from the start in cell culture medium and unsuccessful beyond passage 1 in pleural fluid, and 2  attempts were unsuccessful in both MPE fluid and cell culture medium. These results and the associated pleural fluid cytology as reported by the clinical histopathologist as part of the patient’s routine clinical care are shown in In order to further assess the biological properties of pleural fluid, primary MPM cell culture in MPE fluid was attempted in 6 MPM MPE fluid samples, with concurrent primary cell culture in the standard in vitro cell growth. Despite this, MPM cells proliferated in 100% pleural fluid, to a similar degree in both exudative and transudative MPE fluid. This indicates that it is not simply the quantity of proteins within MPE fluid that gives the fluid the biological capabilities that support cancer cell proliferation in vitro. Furthermore, cancer cells proliferated in heart failure non-MPE transudative pleural fluid. It is possible that the heart failure transudate pleural fluid obtained the contains growth factors since it is a filtrate of blood via capillaries, and therefore is also able to support cancer cell proliferation in vitro. However, the cancer cells might have secreted the necessary growth factors. There have been no good quality studies assessing the components of transudates in this regard.Cell culture is a time-consuming process, requiring several laboratory consumables, and an artificially produced cell culture medium containing a delicate balance of nutrients required for optimal in vitro, by 1.4–2.8 fold and by 1.3–2.2 fold respectively, when compared to serum-free medium as a control  appears to have this effect, and this has potentially significant biological and clinical implications. If pleural fluid continuously bathing pleural cancer cells enables and sustains cell proliferation, the current management approach to MPE will need to be reconsidered. To this end, well-designed prospective clinical studies are now required to determine whether MPE fluid should be drained as early and completely as possible. Further translational studies are required to explore the biological mechanism of cancer cell proliferation when bathed in pleural fluid.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Oxford Radcliffe Biobank Central University Research Ethics Committee (CUREC) number: 19/A107. The patients/participants provided their written informed consent to participate in this study.RA, NK, NR and IP conceived and designed the study. RA and NK did laboratory assays and analyzed the data. XY, MH and TD provided resources and support for the laboratory assays. RA, NR, IP, EB, RM, and MH collected samples and clinical data. RA, NK and IP analyzed clinical data. RA, NK and MD provided resources and prepared the ethics protocols. NR and IP supervised the study. PF and SM supported and facilitating the conduction of the study. All authors contributed to the article and approved the submitted version.This work was supported by an Oxfordshire Health Services Research Committee (OHSRC) Research Grant (ID 1247) and a Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science . NK and NR are supported by a National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) grant. TD is supported by Medical Research Council, UK. XY and MH are supported by CAMS. The views expressed are those of the authors and not those of the NHS, or NIHR.IP was employed by AstraZeneca in a non-related field.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Oesophageal submucosal tumours are usually benign. We report a rare case of esophageal squamous cell carcinoma presenting as a submucosal tumour.A 58-year-old man undergoing screening oesophago-gastroduodenoscopy was found to have a smooth-surfaced 0.6-cm sized submucosal tumour in the oesophagus 30 cm from the incisor. Endoscopic ultrasonography showed the tumour to be located in the muscularis mucosa; the lesion was heterogeneously hypoechoic and had a clear boundary. With a provisional diagnosis of leiomyoma, the tumour was removed by endoscopic submucosal dissection. Pathological examination showed it to be a moderately differentiated infiltrating squamous cell carcinoma, with normal overlying squamous epithelium. Immunohistochemistry indicated that it was caused by malignant transformation in mucosal glandular duct epithelium. Positron emission tomography–computer tomography showed no tumour spread to any other site. The patient was treated by oesophageal resection.The clinician should be aware that oesophageal submucosal tumours with smooth overlying mucosa may not always be benign; malignancy must be ruled out. Oesophageal submucosal tumours originate from mesenchymal tissue and are usually benign. These tumours, which include leiomyoma, stromal tumour, fibroma, and lipoma, are typically covered by normal mucosal epithelium and are usually discovered during oesophago-gastroduodenoscopy (OGD) for other reasons. Oesophageal cancer presenting as a submucosal tumour is very rare. We report a case of oesophageal squamous cell carcinoma mimicking a submucosal tumour.A 58-year-old man whose parents had both died of oesophageal cancer underwent screening OGD and was found to have a smooth-surfaced 0.6-cm sized submucosal tumour in the oesophagus located 30 cm from the incisor Fig. . There wOesophageal squamous cell carcinoma is a primary oesophageal cancer that usually originates in the oesophageal mucosal epithelium. In the early stages, the mucosa may show congestion; clearly delimited area of redness and erosion; and friability, with a tendency to bleed easily. Ulceration of the mucosa and protrusion into the lumen may also occur.Oesophageal cancer presenting as a submucosal tumour with normal overlying mucosa is very unusual. Our literature search revealed only three previous reports over the past 10 years. In 2012, Liu et al. reported a 44-year-old woman with oesophageal submucosal tumour that was removed by endoscopic mucosal resection. Pathological examination of the resected specimen showed a well-differentiated mucoepidermoid carcinoma covered with normal stratified squamous oesophageal epithelium . In 2017Our patient, who did not have any symptoms, underwent routine screening OGD because of the family history of oesophageal cancer. The lesion was only 0.6 cm in size and might easily have been missed. Even when such lesions are discovered, it is common to ask the patient to come for repeat endoscopy, and diagnosis can thereby be delayed. Meanwhile, in view of the related risk factors and epidemiological investigation in the high-incidence area of oesophageal squamous cell carcinoma in China, the patients whose first-degree relatives have a history of oesophageal squamous cell carcinoma are at high risk of oesophageal squamous cell carcinoma , 6.To conclude, an oesophageal submucosal tumor with a smooth surface may not always be benign. Clinicians should be alert to the possibility of malignancy, especially in patients with family history of oesophageal cancer.