An elimination‐rechallenge dietary approach targeting naturally‐occurring bioactive chemicals has been proposed to alleviate functional gastrointestinal symptoms. A major focus of this approach is salicylates. This study aimed to address the potential role of dietary salicylates in the induction of symptoms in patients with irritable bowel syndrome (IBS).versus high‐salicylate diets  was undertaken. All foods were provided containing minimal quantities of other potential food triggers. Gastrointestinal and extraintestinal symptoms were measured daily using a 100‐mm visual‐analogue‐scale.A pilot, double‐blind, randomized, cross‐over trial of 2‐week low‐ P = 0.625; Friedman test). However, clear symptom provocation was seen in the aspirin‐sensitive participant, with all abdominal symptoms and tiredness worsening during the high‐salicylate diet. A similar trend was seen in another participant, where abdominal symptoms gradually worsened during the high‐salicylate diet.Ten participants with IBS completed the study, including one with known aspirin‐sensitivity. Overall, no differences in symptoms were observed .The protocol was registered at  This pilot randomised controlled trial (RCT) provides valuable data regarding the potential use of a diet low in naturally‐occurring dietary salicylates to reduce symptoms associated with common conditions such as irritable bowel syndrome. Worldwide interest in the use of diet as a therapeutic tool in patients with irritable bowel syndrome (IBS) has grown. This attention has been stimulated by the well‐documented induction of symptoms by the ingestion of specific foods,An elimination‐rechallenge dietary approach developed by the Royal Prince Alfred Hospital Allergy Clinic in SydneyOf the multitude of chemicals that are restricted with this approach, salicylates are believed to be a major contributor to symptoms. Thus, in 78% of patients with a range of chronic symptoms who responded to food‐chemical restriction, re‐challenge with salicylates was associated with symptom recurrence,versus high‐salicylate diets in IBS patients.The present study aimed to address the potential role of salicylates in the induction of functional gastrointestinal symptoms by performing a pilot, double‐blind, randomized, cross‐over trial of low‐ Patients with IBS based on Rome III criteriaPotential participants were screened by a gastroenterologist to confirm the diagnosis and to classify according to their predominant bowel habit into diarrhea (IBS‐D), constipation (IBS‐C), or mixed type (IBS‐M). During the 7‐day baseline data‐collection period, all participants were required to record their habitual dietary intake in a detailed food diary. They also recorded symptoms each day during those 7 days. Semiquantitative analysis of their baseline food intake for salicylate and FODMAP contents was performed by two independent dietitians.Participants were then randomized by a computer‐generated order to receive a diet either high or a low in salicylate content for the next 14 days. Participants and investigators were blinded to the diet. After the initial 14 days, the participants undertook a washout period of 7 days, where they resumed their habitual diet. During the washout phase, they completed a diary recording their dietary intake and symptoms. This was followed by a cross‐over to the alternate diet for further 14 days. During the interventional dietary phases, all foods were provided and participants recorded the quantity of the provided foods consumed along with their symptom scores.www.anzctr.org.au (ACTRN12620001250921).Written, informed consent was obtained from all participants prior to commencement of the study. The study protocol was approved by Monash University Human Research Ethics Committee, Monash University, Clayton (Project number: CF14/1642 – 2014000780). The protocol was registered retrospectively at All foods including three main meals, morning and afternoon snacks, and drinks were provided Table . DetaileThe study investigator and two professional chefs prepared all foods. Frozen, complete meals were provided to the participants with instructions to thaw and heat before consumption. The foods were delivered biweekly free of charge to the participant homes. Compliance was monitored via the daily food diaries.The diets were designed based upon the salicylate content of foods determined by in‐house analysis using GC–MS.Both the high‐ and low‐salicylate diets were analyzed for content of energy, macronutrients, fiber, and FODMAPs via FoodWorks 7 . Data on FODMAP content were based on the Monash University FODMAP food composition database.Gastrointestinal and non‐gastrointestinal symptoms were measured daily during the entire course of the study. Abdominal symptoms were measured using the visual analogue scale (VAS), while the fecal symptoms were measured using a Likert scale. On a 100 ‐mm VAS scale, 0 indicates complete remission of symptoms and 100 mm represents worst symptoms. Overall gastrointestinal symptoms, abdominal pain, bloating, passage of wind, and nausea were assessed using the VAS as previously applied.The primary endpoint was the difference in overall gastrointestinal symptoms measured by the 100‐mm VAS on the low‐salicylate diet compared with high‐salicylate diet averaged over the last 3 days of each of the interventional dietary periods. Secondary endpoints included differences between the diets in specific abdominal and extraintestinal symptoms, and differences in symptoms between interventional diets and their respective preceding control phases of baseline or washout. All comparisons were made using average scores of the last 3 days of the respective dietary periods.Both participants and researchers were blinded to the dietary treatments. To assess the success of blinding, at completion each participant was asked to identify their perception of the nature of the diets. As for the researcher, the diets were given a code and it was not revealed until data entry was locked.P value of ≤0.05 was considered statistically significant. Statistical analysis was performed with GraphPad Prism  program.This was a pilot study and hence power calculations were not undertaken. Data were analyzed on an intention‐to‐treat basis. Parametric and nonparametric analyses were used as appropriate. For nonparametric analyses, Friedman test and Wilcoxon signed rank tests were performed to compare the abdominal and fecal symptoms between high‐ and low‐salicylate dietary interventions. The participant recruitment flowchart is shown in Analysis of baseline food intake showed that the participant with known aspirin‐sensitivity was already unknowingly selecting low salicylate foods; this participant had low symptom scores at baseline. Another three participants had very low levels of current symptoms at baseline; these were consuming moderate amounts of salicylates. Four participants had mild to moderate symptoms during baseline and all were consuming high amounts of dietary salicylates. Most of the participants consumed moderate or high amounts of FODMAPs Table . The dieP < 0.001; paired t test]). The total FODMAP content was minimal and did not differ between the diets .The nutritional composition of the low and high‐salicylate diets as consumed by the participants is shown in Table versus low‐salicylate diets are shown in Figure P = 0.625; Friedman test). Likewise, there were no differences in the fecal symptoms (data not shown).Differences in symptoms during the last 3 days of the high‐ Two participants had different levels of abdominal symptoms between the interventional diets. The aspirin‐sensitive participant showed worsening of all abdominal symptoms on the high‐salicylate diet Fig. . The timNo participants had asthma or a skin rash during the study. One participant complained of rhinitis and another mild headache, both during the low‐salicylate diet. Increased tiredness was reported by four participants, three on the low‐salicylate diet and one, the participant with aspirin‐sensitivity, during the high‐salicylate diet.Dietary adherence was 100%, except one participant who was noncompliant to the low‐salicylate diet for 4 days and the high‐salicylate diet for 2 days. Qualitative feedback regarding the palatability of the diets was positive. Eight participants did not correctly identify the low‐ or high‐salicylate diets (including the aspirin‐sensitive participant).While there seems little controversy that aspirin is associated with asthma and urticaria, the strength of data indicating that food‐related salicylates induces abdominal symptoms in patients with IBS is restricted to expert opinion based upon anecdotal evidence. In the current randomized, double‐blind, crossover trial, 2 of 10 participants had different symptom profiles associated with differences in salicylate intake. The first showed convincing moderate to severe symptoms on the high‐salicylate diet and few symptoms on the low‐salicylate diet. Interestingly, this participant habitually consumed a diet low in salicylates and had a previous diagnosis of aspirin‐induced urticaria, although skin lesions were not observed throughout the study. The other participant whose habitual diet was rich in salicylates improved on the low‐salicylate diet and reported worsening of symptoms when the high‐salicylate diet was introduced. Such findings suggest that sensitivity to food‐related salicylates exists but occurs uncommonly and with variable severity.Other observations might support the hypothesis that these two participants were exhibiting salicylate sensitivity. First, both participants showed a pattern of slow induction/alleviation of symptoms over 1 week when exposed to differing amounts of dietary salicylates, consistent with the hypothesis that it is the accumulated tissue concentrations of salicylates that are associated with symptom genesis. According to this theory, the hypersensitive participants can tolerate a particular food chemical until it accumulates and crosses a tolerance threshold beyond which the symptoms manifest.From current dogma, it was anticipated that half of the participants would exhibit salicylate sensitivity. However, five of the participants were in relative remission from IBS symptoms at baseline, despite fulfilling the historical criteria for that diagnosis and their usual diets being moderate to high in salicylate content. In that setting, it would not be possible to show improvement by reducing salicylate intake. While it might also be argued the high‐salicylate diet would be unlikely to induce symptoms because they were already consuming moderate to high dietary salicylates, the diet provided had salicylate content (30 mg/day) greater than that likely to be sourced by the participants. Maximum daily intake has previously been estimated at 13 mg/day.One problem with dietary interventions is collinearity, whereby other changes to dietary composition might be causing or masking symptoms due to the targeted food component. One potential dietary confounder was FODMAP intake. Both experimental diets were, therefore, designed to be low in FODMAPs. Habitual intake indicated moderate intake of FODMAPs by most participants. Thus, lowering FODMAP intake may have masked induction of symptoms by salicylates, although the three participants who were moderately symptomatic did not improve despite the low FODMAP content of the interventional diets. Other dietary components with potential to induce symptoms  were not used in the prepared diets. However, other natural food chemicals, namely glutamates and amines, were present in moderate levels in both diets. If these moderate levels represented a reduction in baseline intake for the participants, this reduction of putatively troublesome dietary factors may have masked symptom induction. However, no participant with baseline symptoms improved on both diets.There have been few studies of dietary restriction in known salicylate‐sensitive conditions. The only cross‐over study reported compared 12 weeks of a low salicylate diet  compared with habitual diet in 10 patients with aspirin‐exacerbated respiratory disease.The current pilot study has limitations. The small number studied, and their heterogeneity of baseline symptoms and salicylate intake limit the interpretation of the results. However, as a pilot, it did show that palatable diets differing in salicylate content can readily be created with its associated high compliance, that nocebo effects are unlikely where the participants studied have little prior knowledge of the putative dietary component, and that salicylate‐sensitive IBS symptoms may well occur if given for a period of greater than 1 week. While the study of patients who believed they were salicylate‐sensitive may have been more appropriate, this would likely to be associated with nocebo responses. Whether altered delivery of salicylates in the diets was achieved may have been enhanced by measurement of serum salicylate concentration at the end of each dietary period, but a very sensitive assay would be needed as only about 3% of dietary salicylate intake is bioavailable.In conclusion, these results have provided some evidence that food‐related salicylates may influence the genesis and/or severity of functional gastrointestinal symptoms in patients with IBS. It will be important to extend this study into a larger cohort to determine the true incidence of salicylate sensitivity in IBS, identify potential markers to predict response, and elucidate mechanisms of action. The lack of discernible placebo and nocebo effects and the palatability of diets differing in salicylate content suggest that blinded cross‐over feeding studies may be a valid way of defining the sensitive population. The observation of a clear effect of varying dietary salicylates in a participant with aspirin‐mediated urticaria suggests that the use of dietary interventions in patients with known aspirin‐mediated medical conditions is worthy of further investigation.AppendixS1. Supporting Information.Click here for additional data file.


The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician‐reported signs  and patient‐reported symptoms . This paper reports consensus decisions from the HOME VII meeting.To complete the core outcome set for AE by agreeing on core outcome instruments for the domains of quality of life (QoL), long‐term control and itch intensity.A face‐to‐face consensus meeting was held in Tokyo, Japan (8–10 April 2019) including 75 participants  from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using predefined consensus rules.It was agreed by consensus that QoL should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children’s Dermatology Life Quality Index (CDLQI) for children and the Infant’s Dermatology Quality of Life Index (IDQoL) for infants. For long‐term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long‐term control. The peak itch numerical rating scale (NRS)‐11 past 24 h was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum.For now, the core outcome set for clinical trials in AE is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments. What is already known about this topic?Core outcomes sets improve the design and reporting of clinical trials, reduce selective outcome reporting bias and facilitate meta‐analysis of results in systematic reviews.The HOME core outcome set for eczema recommends the inclusion of four core domains in all atopic eczema trials: clinician‐reported signs, patient‐reported symptoms, health‐related quality of life (HrQoL) and long‐term control.Clinician‐reported signs should be captured using the Eczema Area and Severity Index (EASI) and patient‐reported symptoms using the Patient‐Oriented Eczema Measure (POEM).What does this study add?The HOME core outcome set is now complete and recommended core outcome instruments have been agreed on for all four domains.Core outcome instruments for HrQoL: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children and Infant’s Dermatology Quality of Life Index (IDQoL) for infants.Core outcome instruments for long‐term control: either the Recap of Atopic Eczema (RECAP) or the Atopic Dermatitis Control Test (ADCT).In addition, itch intensity should be measured using the peak NRS‐11 past 24 h for trials including older children and adults.What are the clinical implications of this work?If all future trials of eczema treatments include the HOME core outcome instruments, then trial results will be more readily incorporated into meta‐analyses in systematic reviews and clinical care will be informed by the best available evidence.Linked Comment: Br J Dermatol 2021; 185:13–14D.F. Murrell and C.F. Paul. . Core outcome sets are considered an essential factor for progressing evidence‐based medicine by permitting studies to be compared and combined in a meaningful way in future systematic reviews and meta‐analyses.HrQoL has been discussed at HOME consensus meetings previously, for adults (HOME IV) and children (HOME V),The domain of long‐term control was the main topic of discussion at the HOME V meeting in Nantes in 2017, where it was agreed that long‐term control should be captured by a combination of repeated measurement of existing core domains , plus a patient global assessment of control. It was recommended that these aspects should be measured repeatedly during trials wherever possible, and that further research was required to agree on a preferred instrument for capturing eczema control, as well as the optimum frequency and timing of assessments.For the symptoms domain, itch intensity had been proposed previously as an important addition to the POEM instrument, which captures frequency of symptoms including itch, but does not quantify itch severity.Achieving consensus over the preferred instruments to complete the HOME core outcome set for AE trials was the focus of discussions at a 3‐day consensus meeting held in Tokyo, Japan (8–10 April 2019) – HOME VII. This report outlines a summary of the consensus recommendations from the HOME VII meeting.Methods used to select outcome instruments for inclusion in the core outcome set were guided by the HOME methodological RoadmapSeventy‐five delegates attended the meeting, plus five observers/translators including 43 (57%) healthcare professionals, 14 (19%) patients/representatives, six (8%) methodologists and 12 (16%) industry representatives (Table Discussions focused on establishing agreement over: (i) preferred instruments for measuring HrQoL in adults and children; (ii) long‐term control in adults and children; and (iii) itch intensity in adults . In addition, discussion of the recommended frequency of data collection and timing of assessments was debated.Small group discussions were used to evaluate content validity and feasibility, using summary cards as prompts to generate discussion and to rank instrument options. Anonymized electronic voting was employed to reach consensus decisions. As with previous HOME meetings, consensus was reached on a statement when fewer than 30% of voters disagreed. Individuals involved in the development of specific instruments were excluded from the vote to avoid conflicts of interest.Full details of the methods used are provided in the published meeting report.Quality of life is a complex, often multidimensional construct that is usually measured by multi‐item questionnaires. At the HOME IV meeting, the HOME initiative voted that psychological functioning, social functioning and physical functioning are essential subdomains for the construct QoL and that there are no other essential subdomains.An updated systematic review of the measurement properties of QoL outcome measures for infants, children and adults with AE was presented.Content validity is recommended as a primary consideration when selecting a core outcome instrument.Whether an instrument could be recommended as the core outcome instrument for QoL was voted on for each age group. Seventy‐two attendees took part in the consensus voting (five conflicted attendees abstained). The Infant’s Dermatitis Quality of Life Index (IDQoL) was voted as the recommended instrument for infants [8 of 70 (11%) disagreed] and the Children’s Dermatology Life Quality Index (CDLQI) for children [6 of 69 (9%) disagreed]. For adults, both the Dermatology Life Quality Index (DLQI) and Skindex were voted as potentially suitable candidate instruments for the core set , but following further discussion and a second consensus vote, the DLQI was chosen as the preferred instrument for adults [11 of 72 (15%) disagreed].In conclusion, the family of instruments, IDQoL, CDLQI and DLQI, which are the most frequently used instruments in the literature, were recommended as the core outcome instruments for the QoL domain in AE clinical trials.A conceptual model for the construct of ‘long‐term control’ was presented and debated ,Quality assessment of the instruments was conducted prior to the meeting according to COSMIN methodology.During the consensus meeting, individual instruments were discussed and ranked in six small groups with a variety of stakeholders in each group. The results of these small group discussions are shown in Table Following whole group discussion and indicative voting, 54 attendees took part in the consensus voting (12 conflicted attendees abstained). ADCT and RECAP were both voted as potential candidate instruments for the core outcome set .It was also recommended that further research should be conducted to develop a single‐item global control instrument that could be evaluated at future HOME meetings.As ADCT and RECAP were both newly developed (and very similar) instruments, with limited validation data to inform a choice between the two, it was agreed that both should be recommended for use as core outcome instruments to measure long‐term control for the time being [12 of 53 (23%) disagreed].No consensus was reached over the preferred frequency of data collection for the domain of long‐term control. This will be discussed at future HOME meetings.Itch intensity was defined as intensity measured by a single‐item instrument, such as a numerical rating scale (NRS), verbal rating scale (VRS) or visual analogue scale (VAS), measured over a specific period of time, e.g. the past 24 h or past week. This subdomain is relevant to adults and children with eczema, with all severities of disease.Evidence was presented on outcome measurement instruments of itch intensity regarding instrument properties and quality of the evidence on measurement properties. Instruments were identified through two systematic reviewsA systematic review of measurement properties for patient‐reported outcome measures of itch intensity included 23 studies on 23 instruments (search 1965–2015).Based on the quality assessment of the instruments and studies using COSMIN methodology, the following single‐item instruments were considered: (i) investigated in patients with itch: NRS‐6 , peak NRS‐11 past 24 h, verbal NRS (VNRS)‐4 , VAS  Only three instruments were validated for eczema in adults, and only for the recall period of the past 24 h. The VAS and VRS past 24 hAfter whole group discussions, 63 attendees took part in the consensus voting. Only five of 63 (8%) disagreed with the statement that itch intensity should be included in the symptoms domain and reported in addition to POEM. All industry representatives refrained from the remainder of the voting due to perceived or potential conflicts of interest with the instruments. It was agreed that peak itch should be measured rather than average itch; only three of 50 (6%) disagreed with including peak itch, whereas 34 of 50 (68%) disagreed with including average itch. The recall period ‘past 24 hours’ for capturing peak itch intensity was preferred with only four of 50 (8%) disagreeing with this timescale compared with more than half disagreeing with using the recall period ‘past week’ .Consensus was reached to include the peak NRS‐11 past 24 hThis recommendation was made only for adults, as there was no validation data available for younger people. However, the group suggested using the instrument for anyone who can self‐report. It is not considered appropriate as a proxy measure.In the future, further validation data on NRS‐11, including in younger people, will be investigated.Discussion over the optimal timing and frequency of data collection for the core outcome instruments was held. Discussions were informed by a pre‐meeting survey, which scoped the views of the wider HOME membership over the preferred timing and frequency of data collection for the core outcome set instruments.It was agreed by consensus that core outcomes should be collected, as a minimum, at baseline and at the time of the primary outcome assessment, which is usually equivalent to end of treatment in trials [none of 72 (0%) disagreed]. No agreement was reached as to the preferred timing of outcome assessments at other timepoints but it was agreed that recommendations (not mandatory) on timepoints for the core outcomes set should be made as part of future HOME activities [nine of 72 (13%) disagreed].During this 3‐day HOME consensus meeting, agreement was reached over the preferred instruments for capturing HrQoL, long‐term control and itch intensity. It was also agreed that outcomes should be recorded as a minimum at baseline and at the time of the primary outcome assessment. These recommendations build on the previously agreed core outcome recommendations and completes the HOME core outcome set for AE.For HrQoL, the preferred core outcome instruments are IDQoL, CDLQI and DLQI for infants, children and adults, respectively.For long‐term control, the RECAP and ADCT outcome instrumentsFuture research and consensus discussions are required to evaluate new QoL instruments as they become available, to explore the use of Patient‐Reported Outcomes Measurement Information System (PROMIS) instrumentsIn considering strengths and limitations, these consensus decisions were conducted over 3 days during a face‐to‐face meeting led by an Independent Chair who had 20+ years of experience of developing core outcomes sets (M.B.). Decisions were made based on the best available evidence, including the results of systematic reviews, surveys of the HOME membership, and international online patient discussion groups conducted prior to the consensus meeting. Our methods were informed by guidance from Outcome Measures in Rheumatology (OMERACT),Because patients and patient representatives represented just 19% of attendees at the meeting, it is possible that some felt it difficult to express their thoughts during the meeting. We strengthened the patient voice by holding a separate session for patients prior to the main meeting and by using small group consensus methods to inform decisions, thus enabling patients to engage more fully. We also had translators working with patients attending the meeting who were unable to speak English.In conclusion, for now, the core outcome set for clinical trials in AE is complete and the specified outcome domains and outcome measurement instruments should be used in all new clinical trials and systematic reviews of AE treatments. Ongoing efforts are required to ensure global uptake of the agreed core outcome instruments. Regulatory authorities, journal editors and funders can play a key role in supporting implementation.Kim S Thomas: Conceptualization ; Data curation ; Methodology ; Writing‐original draft (lead); Writing‐review & editing . Christian Apfelbacher: Conceptualization ; Data curation ; Methodology ; Writing‐original draft ; Writing‐review & editing . Joanne Rachel Chalmers: Conceptualization ; Methodology ; Writing‐review & editing . Eric Lawrence Simpson: Conceptualization ; Methodology ; Writing‐review & editing . Phyllis Spuls: Conceptualization ; Methodology ; Writing‐original draft (supporting); Writing‐review & editing . Louise A.A. Gerbens: Conceptualization ; Methodology ; Writing‐original draft (supporting); Writing‐review & editing . Hywel Williams: Conceptualization ; Methodology ; Writing‐review & editing . Jochen Schmitt: Conceptualization ; Methodology ; Writing‐review & editing . Michael Gabes: Conceptualization ; Methodology ; Writing‐original draft (supporting); Writing‐review & editing . Laura Howells: Conceptualization ; Methodology ; Writing‐review & editing . Beth Stuart: Conceptualization ; Methodology ; Writing‐review & editing . Erin E Grinich: Conceptualization ; Methodology ; Writing‐review & editing . Traci Pawlitschek: Conceptualization ; Methodology ; Writing‐review & editing . Tim Burton: Conceptualization ; Methodology ; Writing‐review & editing . Lynita Howie: Conceptualization ; Methodology ; Writing‐review & editing . Abhijit Gadkari : Conceptualization ; Methodology ; Writing‐review & editing . Laurent Eckert: Conceptualization ; Methodology ; Writing‐review & editing . Toshiya Ebata: Conceptualization ; Methodology ; Writing‐review & editing . Maarten Boers: Conceptualization ; Methodology ; Writing‐review & editing . Hidehisa Saeki: Conceptualization ; Methodology ; Writing‐review & editing . Takeshi Nakahara: Conceptualization ; Methodology ; Writing‐review & editing . Norito Katoh: Conceptualization ; Methodology ; Writing‐review & editing .Table S1 HOME VII participants who contributed to the consensus meeting and voting (8–10 April 2019).Powerpoint S1 Journal Club Slide Set.Click here for additional data file.


Splenic arteriovenous torsion causes splenomegaly and ischemic necrosis of the spleen. The recommended treatment for wandering spleen with hypersplenism is considered to be splenectomy. Splenic arteriovenous torsion causes splenomegaly and ischemic necrosis of the spleen. The recommended treatment for wandering spleen with hypersplenism is considered to be splenectomy. Splenic arteriovenous torsion causes splenomegaly and ischemic necrosis of the spleen. The recommended treatment for wandering spleen with hypersplenism is considered to be splenectomy.A 35‐year‐old Japanese woman had been diagnosed with a wandering spleen 20 years ago. No symptoms such as abdominal pain were observed before the delivery of her full‐term infant. Contrast‐enhanced computed tomography (CE‐CT) was conducted post‐delivery. The patient's spleen was located in the middle of the abdomen (A). A few months post‐delivery, she began to have frequent left‐sided abdominal pain. CE‐CT showed that her spleen had enlarged and moved into the pelvis (B). There is no dislocation of pancreas. The splenic artery and vein were spirally twisted 1260° (C). A laparoscopic splenectomy was performed (D). No abdominal pain occurred post‐surgery. The weight of the removed spleen was 350 g.This was a rare case of wandering spleen with splenomegaly and abdominal pain due to splenic arteriovenous torsion after childbirth. Wandering spleen which moves from the left hypochondrium to other places in the abdominal cavity had been caused by the absence or laxity of splenorenal and gastrosplenic ligaments.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported herein.Informed consent for publication and related images has been obtained from the patient.


BCSbreast conservative surgeryBLISbasal‐like and immune‐suppressedCEF‐Tfluorouracil, epirubicin, and cyclophosphamide followed by docetaxelFUSCCFudan University Shanghai Cancer CenterHRDhomologous recombination deficiencyIMimmunomodulatoryIQRinterquartile rangeLARluminal androgen receptorMESmesenchymal‐likePCbpaclitaxel and carboplatinDear Editor,Triple‐negative breast cancer (TNBC) is associated with genome‐wide instability caused by mutations in homologous recombination repair mechanism,The abovementioned 132 patients in the PATTERN cohort have been enrolled into the Fudan University Shanghai Cancer Center Triple‐Negative Breast Cancer (FUSCC‐TNBC) program to receive whole‐exome sequencing, RNA sequencing, and copy number detection.Clinicopathologic and molecular characteristics were similar between the two arms Figure . FUSCC sp = 0.01), while there was no statistically significant interaction between HRD‐related mutational signature and different treatments (interaction p = 0.19). Then, patients were sorted by their HRD score value regardless of the regimen. In patients with values above the median, PCb was associated with significantly longer RFS compared with CEF‐T , while no evidence of different efficacy was found in the patients with lower HRD scores . Consistently, within the PCb cohort, patients with HRD score above the median had a borderline significantly better RFS than the rest , while no significant difference in RFS was detected in the CEF‐T cohort .Subsequently, we investigated the predictive effect of HRD score and HRD‐related mutational signature. We found the interaction of HRD score and the two different chemotherapy regimens for RFS was significant (interaction p = 0.06), while the outcome of the two cohorts was similar in the rest . No significant difference in RFS was observed between the patients with values above the median and patients with values below the median in the PCb cohort  or the CEF‐T cohort .Although HRD is reversible, mutational signatures would not disappear, even if the defect is no longer active.Additionally, we also investigated the predictive effect of the intrinsic subtype and the FUSCC subtype. Multivariate analyses based on HRD score and HRD‐related mutational signature were also conducted, and the results were consistent with the univariate analysis Table .p = 0.01), but not in those receiving PCb . Association of Reactome glycolysis with worse RFS was also validated in the TNBC patients who received chemotherapy in METABRIC .Furthermore, taking advantage of the RNA sequencing data, we found a couple of hypoxia and glycolysis‐related pathways associated with inferior prognosis in the CEF‐T cohort Figure . This fiIn our study, PCb was related to significantly longer RFS in patients with high HRD score, reflecting an adjuvant carboplatin‐containing regimen might bring more benefits to the TNBC population with high HRD status. By examining the HRD score, the candidate population for adjuvant carboplatin‐containing regimen can be expanded. Consistently, a borderline significant difference in RFS was detected between the two arms in patients with high HRD‐related mutational signature. Considering the limited number of cases involved, we believed that studies with a larger sample size are necessary to determine its effect.Association between upregulation of glycolysis and hypoxia‐related pathways and inferior prognosis in the CEF‐T cohort was observed, and similar results were validated in METABRIC. Metabolic reprogramming is a major hallmark of tumor cells, and chemotherapy‐resistant TNBC cells usually display an enhanced glycolytic phenotype.In conclusion, the HRD score may serve as a biomarker to predict the efficacy of an adjuvant carboplatin‐containing regimen for TNBC. Upregulation of glycolysis and hypoxia‐related pathways was associated with inferior prognosis of patients treated by adjuvant anthracycline/taxane regimen. Whether metabolic alterations participate in resistance needs to be further studied, and relevant treatment strategies are worth exploring.Supported by grants from the National Natural Science Foundation of China , the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100).The authors declare that no conflict of interest exists.The independent institutional review board of the participating centers approved the PATTERN study protocol. We performed the study according to the International Conference on Harmonisation Good Clinical Practice guidelines and ethical principles of the Declaration of Helsinki. All patients provided written informed consent.Consents for publication were obtained from all patients.Microarray data and sequence data were deposited in the NCBI Gene Expression Omnibus  and Sequence Read Archive . The data that support the findings of this study are available from the corresponding author upon reasonable request.Supporting informationClick here for additional data file.


Restoration ecology has historically focused on reconstructing communities of highly visible taxa while less visible taxa, such as invertebrates and microbes, are ignored. This is problematic as invertebrates and microbes make up the vast bulk of biodiversity and drive many key ecosystem processes, yet they are rarely actively reintroduced following restoration, potentially limiting ecosystem function and biodiversity in these areas.In this review, we discuss the current (limited) incorporation of invertebrates and microbes in restoration and rewilding projects. We argue that these groups should be actively rewilded during restoration to improve biodiversity, ecosystem function outcomes, and highlight how they can be used to greater effect in the future. For example, invertebrates and microbes are easily manipulated, meaning whole communities can potentially be rewilded through habitat transplants in a practice that we refer to as “whole‐of‐community” rewilding.We provide a framework for whole‐of‐community rewilding and describe empirical case studies as practical applications of this under‐researched restoration tool that land managers can use to improve restoration outcomes.We hope this new perspective on whole‐of‐community restoration will promote applied research into restoration that incorporates all biota, irrespective of size, while also enabling a better understanding of fundamental ecological theory, such as colonization and competition trade‐offs. This may be a necessary consideration as invertebrates that are important in providing ecosystem services are declining globally; targeting invertebrate communities during restoration may be crucial in stemming this decline. Restoration and rewilding projects have historically overlooked the role played by invertebrates and microbes in restoring ecosystems. Here, we review the current state of microbial and invertebrate rewilding projects and provide recommendations on how projects can move forward in the future. In efforts to ameliorate our impact, we invest billions into ecological restoration each year to repair environments  , we discuss scenarios in which invertebrate and microbial rewilding is justified during restoration. Finally, we discuss how invertebrate and microbial rewilding can move forward in the future by utilizing their unique characteristics. This includes specific examples of empirical invertebrate and microbial rewilding projects that land managers can use during restoration to improve the recovery of ecosystem functions and biodiversity. Our goal is to challenge the current plant‐focused view of restoration and provide the foundations for a more holistic approach that better values the role of invertebrates and microbes during ecosystem recovery.3The return of invertebrates to revegetated areas is crucial for restoration goals as they are critical components of functioning ecosystems. Invertebrates may fail to actively recolonize due to inadequate habitat within the restoration site or characteristics that limit dispersal, such as a lack of wings , potentially offering an avenue for community restoration. Several studies test the impacts of inoculating restoration sites with soil taken from target areas    projects. Because invertebrates and microbes are miniscule, whole communities can be easily transported within small transplants of habitat containing a multitude of species, individuals, and propagules—bypassing the slow species‐by‐species reintroductions seen in current restoration practices Corlett, . This is8There are, however, risks associated with whole‐of‐community rewilding that need to be acknowledged and addressed. Land managers should be aware of the potentially detrimental effects on remnant sites that this form of rewilding may have if it were unregulated. For example, the repeated removal of habitat from remnant areas during the rewilding event might diminish source populations of invertebrates and microbes or degrade habitats. This is especially true if the microclimatic and biotic conditions of the new restoration site are unsuitable for the transplantees as they will likely perish, meaning the only outcome of the transplant is a diminishment in source populations as opposed to an increase in their range. This could be remedied by regulation of the harvesting in space and time, for example, by spreading the collection event over various areas within the remnant sites, ensuring that (a) source populations are not depleted; (b) transplanted populations capture the breadth of diversity and life history stages in natural communities; and (c) interacting co‐dependent taxa are introduced together.Land managers will also need to be conscious of the potential to spread invasive invertebrates and microbes during the rewilding event as non‐natives may be embedded within remnant sites. Even though remnants sites would ideally be “pristine,” thorough sampling of the source population prerewilding is needed to assess the risks of spreading invasive species into areas in which they may not be present. The introduction of invasive species or pathogens is a risk for all reintroduction projects, regardless of whether they are single species or whole‐of‐community reintroductions. Rewilding should therefore only occur when natural recolonization seems to be impossible or exceedingly slow . At least two independent studies have reported beneficial plant growth outcomes even when the inoculant was lost from the soil . They both deplete SOC through respiration and accumulate SOC through growth and by stabilizing soil aggregates  of a local paddock tree and scattering this around the base of revegetated plants Figure . Local p11Although the emphasis of whole‐of‐community rewilding often falls on reinstating function Table , it may 12If ecological restoration is to move forward as a more complete science, it is critical that we further investigate the role that rewilded invertebrates and microbes play during restoration. Recent advances in the field of restoration ecology have explored both the potential of whole‐of‐community rewilding as a restorative tool ; writing–original draft (lead); writing–review and editing (lead). Jennifer L. Wood: Conceptualization (supporting); writing–original draft (lead); writing–review and editing (supporting). Nicholas P. Murphy: Conceptualization (supporting); writing–review and editing (supporting). Heloise Gibb: Conceptualization (lead); writing–original draft (lead); writing–review and editing (lead).


In the past 15 years since its inception, Microbial Biotechnology (MBT) has been a top journal in microbial technology. MBT is committed to promoting innovative, diverse and socially beneficial microbial technology research. It provides a platform for researchers to share innovative research and cutting‐edge ideas. Even minor technological advances will undoubtedly promote the application of microbial technology in the future.From the perspective of nature and humans’ sustainable development, waste recycling and pollutant removal are two critical research areas. In the past 20 years, the application of biotechnology in these two aspects has made remarkable achievements. Since the breakthroughs of DNA sequencing technology in 1976 and its third generation in 2011, the rapid development of sequencing technology has dramatically promoted the detection capability of environmental micro‐organisms. It deepens people’s understanding of microbial metabolism and inter‐species relationship, thereby accelerating the application of microbial technology in the environmental field. Over the next 15 years, various genomic technologies and novel high‐throughput isolation and culture methods will be used to accelerate the exploration of our biosphere, which will further promote the application of microbial biotechnology.et al., et al., et al., ‐1 , ethyl butyrate, polyhydroxyalkanoate (PHA) and other products, which are essential raw materials for medical treatment, food, cosmetics and biodegradable plastics (Donno Novelli pahAc) to trans‐o‐hydroxybenzylidenepyruvate hydratase‐aldolase gene (pahE) to detect the species and activity of aerobic PAHs‐degrading micro‐organisms in various environments. pahE led to much higher detection accuracy and more accurate correlation with PAHs degradation efficiency, facilitating water or soil remediation by biotechnology on the earth is one of the most severe environmental problems. Among the POPs, petroleum hydrocarbons, polycyclic aromatic hydrocarbons (PAHs) and halogenated hydrocarbons are the major environmental pollutants that threaten human health because of their high hydrophobicity and high toxicity. Over 20 years of effort paved the significant development in research about aerobic PAHs‐degrading micro‐organisms. According to the incomplete statistics of previous studies, over 100 genera of bacteria were verified to grow with different PAHs as the sole carbon source under aerobic conditions, and the major aerobic PAHs biodegradation pathways, degradation genes and enzymes were intensively studied. Meanwhile, functional gene markers were further extended from the PAHs ‐hydrolating dioxygenase large subunit gene (In conclusion, the increasing public concerns of the environment has promoted the rapid development of new microbial technologies, focusing on solving environmental problems and maximizing the development of biological resources available to human beings. Many challenges and even more exciting breakthroughs are expected in the development of environmental microbial technology over the next 15 years.


Understanding the influences on healthcare professionals’ career choices and progression can inform interventions to improve workforce retention. Retention of health professionals is a high priority worldwide, in order to maintain expertise and meet the needs of national populations. In the UK, investment in clinical scientists’ pre-registration education is high and the need to retain motivated scientists recognised.We conducted a mixed methods study to investigate the career choices and progression of early career clinical scientists. First job sector and salary of trainees who completed the UK pre-registration Scientist Training Programme (STP) between 2014 and 2019 were analysed using descriptive statistics and Chi-Squared tests. Semi-structured interviews conducted with volunteer practising clinical scientists who completed the programme in 2015 or 2016 were analysed thematically and reviewed for alignment with theories for understanding career choice and workforce retention.Most scientists who completed the STP between 2014 and 2019 obtained a post in the UK National Health Service (NHS) and achieved the expected starting salary. Life scientists were more likely to work in non-NHS healthcare settings than other scientific divisions; and physiological scientists less likely to achieve the expected starting salary. Experiences during training influenced career choice and progression 0–3 years post qualification, as did level of integration of training places with workforce planning. Specialty norms, staff turnover, organisational uncertainty and geographical preferences influenced choices in both the short (0–3 years) and longer term (5 + years). Interviewees reported a strong commitment to public service; and some could foresee that these priorities would influence future decisions about applying for management positions. These factors aligned with the components of job embeddedness theory, particularly that of ‘fit’.Training experiences, personal values, specialty norms and organisational factors all influence UK clinical scientists’ early career choices and progression. Job embeddedness theory provides a useful lens through which to explore career choice and progression; and suggests types of intervention that can enhance the careers of this essential group. Interventions need to take account of variations between different scientific specialties.The online version contains supplementary material available at 10.1186/s12913-021-07064-1. High quality patient care depends in large part on the expertise and morale of the health workforce ; and heaUnderstanding the influences on health professionals’ career choice and progression can inform efforts to improve retention . HoweverIn the UK, as in other countries, clinical scientists make up a significant proportion of the healthcare science workforce . HealthcThe UK Scientist Training Programme (STP) is a three-year post-graduate pre-registration programme for aspiring clinical scientists. It involves a remunerated training post blended with a Master’s degree in clinical science. Trainees specialise in one of 30 specialties within four scientific divisions: life sciences, physical sciences, physiological sciences and bioinformatics . All traOur exploratory study has sought to answer the following questions: how have the careers of early career clinical scientists developed since they completed the STP; how do their career destinations so far compare with their aspirations; what factors have influenced their career choices to date; and how do they see their career developing over the next 5 years? For our mixed-method exploratory investigation , participants were early career clinical scientists who completed the Scientist Training Programme (STP) between 2014 and 2019.Data from the annual STP exit surveys for 2014–2019 were analysed to identify newly qualified scientists’ first job sector and salary. Chi-squared tests (SPSS Statistics version 24 (IBM)) were used to test whether associations between variables were significant: p-values < 0.05 were considered significant.Semi-structured interviews were held between June and December 2018. The National School of Healthcare Science (NSHCS) invited individuals who completed the STP in 2015 and 2016 and therefore had 2–3 years early career experience to volunteer for the study via email. To reduce the risk of identification, only individuals from specialties with more than eight trainees a year were invited. Volunteers registered their interest by emailing the contact address of the research group. Interview questions explored scientists’ career choice and progression to date and their future career plans see .Interviews were recorded, transcribed intelligence verbatim (i.e. ‘filler’ words e.g. ‘erm’ and repeated words or phrases were removed) and analysed thematically, following Braun and Clarke’s six stages . TranscrThemes were reviewed for alignment with Bronfenbrenner’s socio-ecological model of human development  and withn = 1226) of completing trainees returned the STP exit survey.Between 2014 and 2019, 88 %  = 35, p < .001). This appears to be due to variation in the percentage of completers staying in or leaving the NHS; 82 % of life scientists stayed compared to 90 % of physiological scientists. More than a tenth (11 %) of those from life sciences gained employment in a non-NHS healthcare setting, compared to 4 % from bioinformatics, 4 % from physical science and 3 % from physiological sciences.Most survey respondents (86 %) reported first post STP employment with the UK NHS Fig. . Job secMost completers whose first post was in the NHS reported receiving the expected Band 7 salary (67 %), whilst a third (31 %) remained on Band 6. Salaries for those whose first post was outside the NHS were more variable, with 20 % of those entering non-NHS healthcare settings receiving a Band 8 equivalent and 9 % reporting a decrease in salary.2 = 225, p < .001). This appears to be primarily due to lower starting salaries in the physiological sciences: 64 %, 77 % and 90 % of respondents from bioinformatics, life and physical sciences respectively commanded salaries at Band 7 compared to 37 % in physiological sciences. Consequently, more respondents from physiological sciences either remained on Band 6 compared with the other divisions or decreased to Band 5  completers who qualified between 2014 and 2019 obtained a first post in the UK National Health Service (NHS) and achieved the anticipated salary (AfC Band 7). Some variation between scientific divisions was apparent: life scientists’ first job sector was less likely than other divisions to be the NHS; and physiological scientists were less likely to achieve the expected rise in salary.Interview responses indicated that experiences during training influenced career choice and progression. Exposure to new specialty areas during training could spark an interest that altered an individual’s career path; and enthusiastic, skilled and engaged training officers were a major influence on trainees’ thinking about their careers, providing role models, mentoring and creating opportunities for learning.The extent to which STP training places aligned with demand for qualified scientists influenced career choice and progression on immediate qualification. Specialty norms, staff turnover, organisational uncertainty and personal factors such as preference for geographical location influenced them in both the short (0–3 years) and longer term (5 + years). Many interviewees reported a strong commitment to an ethos of public service, patient care and a desire to ‘give something back’ in return for their training and opportunities. This could explain why a high proportion of completers entered first employment in the National Health Service. In the future, some could foresee that these priorities would influence their decisions about whether or not to apply for a management and leadership position that would take them away from clinical work.Mitchell’s job embeddedness theory offers a framework for understanding why ‘embedded’ individuals are more likely to remain in an organisation , 12. TheSalary and opportunities for career progression varied across scientific specialities: trainees from the physiological sciences formed a substantial proportion of the 31 % of STP completers who did not achieve the expected salary on qualification; and some interviewees, particularly those from audiology, reported lower starting salaries and slower career progression than their peers in other specialties. This suggests that clinical science is a diverse group that is still influenced by historical speciality norms, despite recent initiatives to standardise training and career opportunities for healthcare scientists . While sAlthough many interviewees expressed a desire to work in the NHS, some felt that this was not an option open to them. This may reflect competing personal priorities, such as preference for a geographical location with limited availability of NHS posts. Organisational factors, including governmental priorities for outsourcing scientific services  and the Influences on the career choices and progression of clinical scientists are similar to those identified for doctors. Experiences during training and exposure and role modelling within the specialty influence doctors’ choices –26, as dOur study suggests a need to enhance integration of clinical scientist training posts with NHS workforce planning. This complex task will require understanding of the perspectives and priorities of organisational stakeholders, as well as those of individual scientists. The parallels that we have observed between the clinical sciences and medicine suggest that mechanisms for ensuring medical training-workforce integration may be transferable to the clinical sciences; and leaders at the National School for Healthcare Sciences advocate the introduction of Scientific Directors at Trust Board level, akin to those already in place for medicine, to provide similar leadership and profile.. Investigation of all these aspects would be an appropriate follow up to our study.Our study has a number of limitations. Our focus on interviewing scientists who had been in practice for at least 2–3 years meant that we were unable to obtain information from the small number of scientists in the then relatively new bioinformatics division. Although our sample of 13 interviewees included at least one scientist from each of the other three divisions, it was not possible to sample all scientific specialties. Our study is a snapshot of choices and progression at a particular career stage, and we acknowledge that such choices may change as careers develop over the longer term. Although the concept of job embeddedness has been questioned , it was Our findings are encouraging for educators and workforce managers working to improve retention of skilled and motivated clinical scientists. They suggest that attention to variation in training experience, the quality of trainee mentoring and supervision and better integration of training places with likely workforce demand will pay dividends, as will maximising the ‘fit’ between individuals and their organisation. However, variation between specialties will need to be considered when developing interventions.Training experiences, personal values, specialty norms and organisational factors all influence UK clinical scientists’ early career choices and progression. These factors align with concepts within job embeddedness theory, particularly that of ‘fit’. Job embeddedness provides a useful lens through which to explore career choice and progression; and suggests types of intervention that can enhance the careers of this essential group. Interventions need to take account of variations between different scientific specialties.Additional file 1


Dear editor:The abnormality of intracellular cancer‐related signal pathways is a critical factor for the emergence of retinoblastoma (RB).The dCas9‐based molecular sensor acted as the center of intracellular reprogrammed signaling pathways to control endogenous proteins. The single guiding RNA (sgRNA) was engineered by integrating aptamersOne hypothetical use of molecular sensors is to link oncogenic signals to anticancer pathways. Nucleophosmin (NPM)Bax gene promoter. To induce β‐catenin sensors to only trigger the expressions of downstream genes of interest without disturbance from dCas9 and their fusion proteins, the MS2 hairpinsBcl2 gene, and the AFP hairpinBCL2 gene, and β‐catenin sensors were used to activate the expression of the Bax gene (Figure We then determined that molecular sensors could redirect the native signal pathways through multiple specific input signals in the corresponding cells to establish an artificial signal network. NF‐κBe Figure . The duae Figure .As a potential genetic device, molecular sensors regulated the biological behavior of RB cells by redirecting the signaling pathways of cancer cells, which may have clinical value. They were able to switch between the on state and off state by freely sensing the presence or absence of target input molecules, and they showed dose dependence of the input molecules. These characteristics all showed that these molecular sensors possessed excellent ability to control and model various systems. Although there are still some challenges in the development of clinically effective treatments for RB treatment model based on molecular sensors, this novel approach is expected to be extended to the treatment of other malignant tumors or the regulation of other cell biological processes.All authors declare that there is no conflict of interest.Supporting informationClick here for additional data file.


To compare the location of suspect lesions detected by computational analysis of multimodal magnetic resonance imaging data with areas of seizure onset, early propagation, and interictal epileptiform discharges (IEDs) identified with stereoelectroencephalography (SEEG) in a cohort of patients with medically refractory focal epilepsy and radiologically normal magnetic resonance imaging (MRI) scans.We developed a method of lesion detection using computational analysis of multimodal MRI data in a cohort of 62 control subjects, and 42 patients with focal epilepsy and MRI‐visible lesions. We then applied it to detect covert lesions in 27 focal epilepsy patients with radiologically normal MRI scans, comparing our findings with the areas of seizure onset, early propagation, and IEDs identified at SEEG.Seizure‐onset zones (SoZs) were identified at SEEG in 18 of the 27 patients (67%) with radiologically normal MRI scans. In 11 of these 18 cases (61%), concordant abnormalities were detected by our method. In the remaining seven cases, either early seizure propagation or IEDs were observed within the abnormalities detected, or there were additional areas of imaging abnormalities found by our method that were not sampled at SEEG. In one of the nine patients (11%) in whom SEEG was inconclusive, an abnormality, which may have been involved in seizures, was identified by our method and was not sampled at SEEG.Computational analysis of multimodal MRI data revealed covert abnormalities in the majority of patients with refractory focal epilepsy and radiologically normal MRI that co‐located with SEEG defined zones of seizure onset. The method could help identify areas that should be targeted with SEEG when considering epilepsy surgery. Computational analysis of multimodal magnetic resonance imaging (MRI) data can help localize the seizure‐onset zone (SoZ) in patients with medically refractory focal epilepsy and radiologically normal MRIComparison with the areas of seizure onset, early propagation, and interictal epileptiform discharges (IEDs) identified at SEEG represent a direct means of validationThe method may aid refining the hypothesis for SEEG implantation1Surgical intervention in medically refractory focal epilepsy is only recommended if the area of the brain responsible for seizures can be reliably localized and safely resected. The ideal clinical scenario is if a lesion, found on magnetic resonance imaging (MRI), is confirmed to be involved in seizures by clinical consensus and the risk‐to‐benefit ratio of resecting the brain area responsible is favorable. In 20%–40% of individuals with medically refractory focal epilepsy, no relevant abnormality is visualized on MRI (“MRI‐negative”).Recent research has shown that subtle imaging abnormalities that are not evident on visual reading exist in many individuals with MRI‐negative epilepsy,Most current computational neuroimaging methods are focused on detection of focal cortical dysplasia (FCD), but numerous other pathologies also need consideration. There is also a need to gain specificity, which may be achieved by combining information provided by multimodality imaging.To address these issues, we have developed a method of lesion localization based on the computational analysis of regional and voxel‐based brain MRI features from multimodal MRI data that is not specific to any type of lesion. Our imaging protocol included T1‐weighted imaging, fluid‐attenuated inversion recovery (FLAIR) imaging, susceptibility weighted imaging, multi‐shell, diffusion‐weighted imaging allowing diffusion tensor imaging (DTI) analysis218F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) and single‐photon emission computed tomography (SPECT). We included patients with normal MRI on visual reading by neuroradiologists specializing in epilepsy who were recommended for SEEG. The study was approved by the NHNN and University College London (UCL) Queen Square Institute of Neurology Joint Ethics Committee. All subjects gave written, informed consent before participating in the study.This was a prospective study recruiting patients with medically refractory focal epilepsy undergoing presurgical evaluation at the National Hospital for Neurology and Neurosurgery (NHNN), London, UK, and control subjects. The diagnosis was established by clinical consensus during a multidisciplinary team meeting considering history and seizure semiology, 3 T structural MRI with an epilepsy protocol, prolonged video‐EEG telemetry, and neuropsychology. Additional investigations, where relevant, included One hundred thirty‐one subjects were recruited: 62 healthy controls  with no history of neurological or psychiatric disease, and 69 patients with medically refractory focal epilepsy Table . Of the reg) trained on features of the brain on a per parcellated brain region basis, whereas the second GBDT was a LightGBM classifier (C2vox) trained on voxelwise brain features in standard Montreal Neurological Institute 152 (MNI152) space. The workflow is shown in Figure We developed a computational method of lesion detection, comprising two stacked gradient boosting decision tree (GBDT) LightGBM reg and C2vox. We subsequently used the two classifiers/regressors to check for the presence of any covert abnormalities in the MRI‐negative cases. Computationally detected abnormalities were not used to influence the presurgical evaluation of patients including the planning of SEEG.In the case of the MRI‐positive patients, lesions were outlined by an epileptologist (GPW) using the T1‐weighted and the FLAIR scans , DTI axial diffusivity (AD), DTI fractional anisotropy (FA), and DTI radial diffusivity (RD)  Table . The DESvox was trained to learn a mapping from the signal intensity of each voxel, on each input volume, together with its six immediate neighbors in three dimensions (3D) to a target value of 1 or 0, depending on whether the central voxel fell within an area marked as lesional or nonlesional. For control subjects, all voxels had a target value of 0, indicating the absence of lesions. The predicted lesion mask was subsequently transformed back to the space of the original T1‐weighted scan using inverse transformation.C22.3vox. For control subjects, we assessed whether any false positive voxels were detected.For MRI‐positive patients, we used the leave‐one‐out cross‐validation scheme and measured lesion detection performance using the dice score coefficient (DSC). DSC is a measure of spatial overlap and was calculated between the ground truth lesion masks and the output from C2vox and the results of SEEG. A sphere of 10 mm diameter was drawn and visualized in 3D using EpiNavvox. The following were then noted by consensus agreement between an epileptologist (JD), a neurophysiologist (FAC), and two senior research fellows (RR and BK): whether the SoZ was within an area marked as abnormal by C2vox, whether there was early seizure propagation within the areas marked as abnormal by C2vox, whether there were interictal epileptiform discharges within the areas marked as abnormal by C2vox, whether there were areas marked as abnormal by C2vox that were not sampled by the SEEG electrodes, and whether there were areas marked as abnormal by C2vox that were sampled by the SEEG electrodes but did not give rise to seizures.For MRI‐negative patients, we made a principled comparison of the output from C23vox was 0.59 (IQR: 0.37–0.78), measured using the leave‐one‐out cross‐validation scheme. The median over all MRI‐positive cases of the sensitivity and specificity of voxelwise lesion detection were 0.55 (IRQ: 0.21–0.81), and 0.9997 (IRQ: 0.9994–0.9999). An example case is shown in Figure In the MRI‐positive cases, the median DSC, measuring the degree of spatial overlap between the manually drawn lesion masks and the lesions detected by C29 IQR: 0.7–0.78, mGrouped by pathology, the overall spatial agreements were 0.78 (IQR: 0.74–0.82) for hippocampal sclerosis, and 0.38 (IQR: 0.11–0.49) for other pathologies. For the latter group, there was no clear relationship between the pathology identified on radiological inspection and the DSC value.A case with low spatial agreement is shown in Figure reg) by withholding the output from it from C2vox and observed an approximate decrease in DSC of 6% over all MRI‐positive cases. The corresponding decreases in sensitivity and specificity were 10% and 0.01%.We also evaluated the value of the first‐stage classifier  and second‐stage classifiers (C2vox) are amalgamations of the information contained in all the input modalities. We observed that the T1‐weighted image had a relatively small contribution to the output of C2vox having already been used for structural assessment by C1reg.In comparison, the decreases in spatial agreement measured in terms of the dice score coefficient upon separately removing each modality as input to C2D Figure . We notevox‐detected lesion masks .Across all MRI‐positive cases, there was not a significant systematic difference between the lesion volumes measured using the manually drawn and the C2No lesional areas were detected in any of the 62 control cases.vox . Of the four patients in this group who had surgery, one had a right temporal resection with an International League Against Epilepsy (ILAE) outcome of 5 at 12 months. The patient had multiple pathologies found on ex vivo inspection of the excised tissues . One patient had a right frontal resection with an ILAE outcome of 1 at 12 months (case 1). This was the only case in group A that had false positives, identified as additional abnormal areas found by C2vox that were sampled at SEEG but did not give rise to seizures  of the 27 patients Figure . In 11 . However, in all seven cases, there was either early seizure propagation and/or interictal epileptiform discharges within the abnormal areas detected by C2vox  and/or additional abnormal areas were found by C2vox that were not sampled by the intracranial electrodes . Only one patient in this group had surgery (case 3). No specific pathology was identified on ex vivo inspection of the excised tissues for this patient, who had a right frontal resection. Their ILAE outcome was 3 at 12 months. This patient also had additional abnormal areas detected by C2vox, which were not sampled at SEEG.In the remaining 7 (39%) of the 18 of the cases for which SEEG was conclusive, the SoZ found at SEEG was not within the abnormal areas detected by C2vox that were sampled by the SEEG electrodes but did not give rise to seizures in 6 (33%) of the 18 cases for which SEEG was conclusive. However, in all these cases, there was early seizure propagation and/or interictal epileptiform discharges found within the detected areas .For the patients who had postsurgical outcome data available and had abnormalities found by C2vox in this case.SEEG was inconclusive in 9 (33%) of the 27 MRI negative cases . In one patient (case 18), ictal and interictal scalp video‐EEG was suggestive of left temporal onset, but no spontaneous seizures were captured on SEEG. Amygdala stimulation elicited a seizure with similar semiology and although not absolutely specific, the clinical consensus was a mesiotemporal onset for which left temporal resection was undertaken with an ILAE outcome at 12 months of 5. There were interictal epileptiform discharges during SEEG within the abnormal areas detected by C2vox that were not sampled at SEEG, which may have helped localize the epileptogenic zone  of the nine cases for whom SEEG was inconclusive.Overall, there was early seizure propagation and/or interictal epileptiform discharges within the abnormal areas found by C24Medically refractory focal epilepsy presenting with radiologically normal MRI is a major clinical challenge.In the patients with medically refractory focal epilepsy and radiologically normal MRI with a SoZ identified at SEEG, the majority  had a SoZ within the abnormal areas detected by our method. In those where this was not the case, most  demonstrated early seizure propagation and/or interictal epileptiform discharges within the abnormal areas found by our method, suggesting that the approach offers promise. This was also true for patients in whom a SoZ was not located at SEEG where this value was 6/9 or 66%.reg assesses each parcellated region of the brain separately and produces a probabilistic, regional brain abnormality map. The second‐stage classifier (C2vox) then integrates this regional brain abnormality map, alongside the available MRI data, into a voxelwise, probabilistic map of brain abnormalities. The rationale behind this approach is that epilepsy can result not only from an abnormality of a specific brain region  but also from abnormalities that span across more than one area of the brain . Although both types of abnormalities can be detected in a voxelwise manner, our results support the hypothesis that regional abnormalities may be best detected with input from a prior, regional assessment: withholding of the output from C1reg as an input to C2vox resulted in a decrease in DSC of ~6% for the MRI‐positive cases.Our method uses a two‐stage detection scheme. Our C1Our comparison of the computationally detected abnormalities with SEEG data enables us to assess whether these areas give rise to epileptic seizures, and/or are involved in early seizure propagation, and interictal epileptiform discharges.n = 42) we used to train our system. However, despite this limitation, we observed a promising degree of covert epileptogenic lesion detection in radiologically normal, medically refractory focal epilepsy. We continue to enroll patients in our program, and with a developing imaging database comprising a diverse range of underlying pathologies, we hope to increase the strength of our technique. A growing imaging database will also enable us to test the hypothesis that the underlying pathology  may also be inferred from multimodal MRI data.Our study has limitations. The first of these is the limited number of MRI‐positive lesional cases (N = 5). Future evaluation would benefit from a larger number of postoperative outcomes, and a prospective assessment of the utility of the method in planning SEEG coverage.The second limitation of our study is the small number of surgical outcomes that were available. This was due partly to the high attrition rate  following SEEG, and partly due to the ongoing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic, which meant that some surgeries had to be put on hold , and the normalization of raw image volumes . Furthermore, the flexibility offered by machine learning makes our method capable of modeling‐out batch effects when it is expanded to a multi‐center setting by means of utilizing batch‐related parameters  as additional variables.vox (7/18 or 39%) and to allow us to quantitatively assess whether agreement between the two improves postsurgical outcomes. In the present study, we have found qualitative evidence suggesting that in cases in whom postsurgical outcome data are available, and there are additional abnormalities found by C2vox,which are not sampled at SEEG, the outcome may be suboptimal. Further work will determine whether taking into account the abnormalities detected by C2vox when planning SEEG can increase the number of occasions in which curative surgery can be offered to patients and improve postsurgical outcomes for those who undergo surgery.Further development of our imaging database is expected to reduce the number of cases in whom the seizure focus found at SEEG does not collocate with the abnormal areas found by C2vox, which were not sampled at SEEG, and the consideration of the computationally detected abnormalities might have helped refine the SEEG sampling strategy and identify the SoZ.In our study, SEEG was inconclusive in 9 of 27 patients (33%). In one patient this was due to the absence of any spontaneous seizures during SEEG, whereas a clear SoZ could not be identified in the remaining eight patients. These cases remain a challenge. However, as the imaging database grows, covert abnormalities in such cases may become detectable. Also of note is that one of these patients had abnormal areas found by C2Because contemporary computational methods may offer the possibility of delineating the full extent of lesions extending beyond what is visible on conventional MRI, the additional information obtained from such methods may also help in the pre‐surgical evaluation of MRI‐positive cases. However, the focus of the present study was the 27 cases with no visible MRI lesions where the 42 cases with visible lesions were used as a training set to develop the computational method.A comparison to existing published computational methods would be welcome but challenging due to differences in patient cohorts and assessment criteria. Our approach aims to detect any type of lesion, whereas other voxel‐based techniques5Computational analysis of multimodal MRI data may help in identifying epileptogenic lesions in medically refractory focal epilepsy, and radiologically normal MRI. Comparison with the areas of seizure onset, early propagation and interictal epileptiform discharges found with SEEG helps validate the method used for the detection of the covert lesions. Further work, including the building of a large database of MRI‐positive lesional cases, is expected to improve the value of the technique and determine whether consideration of the computationally detected lesions in intracranial EEG and surgical planning can increase the number of patients that can be offered surgery, as well as improve post‐surgical outcomes.GJB receives honoraria for teaching from GE Healthcare. The other authors have no disclosures or conflicts of interest to report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.Supplementary MaterialClick here for additional data file.


While cigarette smoke compounds are known to have immunosuppressive effects on the oral mucosa, the relationship between in vivo immune dysfunction caused by smoking and the development of oral Candida infections remains largely unexplored. In a recent issue of The Journal of Cellular and Molecular Medicine, Ye and colleagues provide evidence that smoking increases oral mucosa susceptibility to Candida albicans infection via the activation of the Nrf2 pathway, which in turn negatively regulates the NLRP3 inflammasome. This opens new perspective in considering Nrf2 as a relevant target for smoking‐induced C. albicans‐related oral diseases. Cigarette smoke (CS) contains a complex mixture of oxidants and numerous reactive oxygen species (ROS) predisposing humans to several mild‐to‐severe oral health problems, including oropharyngeal candidiasis (OPC) and oral leukoplakia (OLK). OPC, commonly referred to as ‘thrush’, corresponds to infections of various oral mucosal sites and is characterized by Candida yeasts overgrowth and invasion of superficial tissues while OLK encompasses white patches or plaques potentially malignant that develops in the oral cavity. Oxidative stress and imbalance of the cellular redox state induced by smoking can change the oral microbiome and damage the structure and function of the oral epithelial barrier, the first‐line defence against fungal infections.A preliminary series of experiments first confirmed what was expected, reporting that smoking is able to enhance the proliferation of C. albicans in experimental and clinical models. The growth of C. albicans was accompanied by a marked oxidative stress on epithelial cells revealed not only by an accumulation of ROS and malondialdehyde but also by a decrease in reduced (GSH) and oxidized (GSSG) glutathione ratio (GSH/GSSG) in both CS extract‐treated C. albicans and immortalized human oral mucosa epithelial cells Leuk1) co‐culture and CS‐treated rat infection models. Nrf2 is well documented to act in epithelial cells as an oxidative stress–sensing protein that controls over 100 genes by recognizing the antioxidant response element enhancer sequence. Here, Ye and colleagues found that in response to oxidative stress generated by smoking, Nrf2 is phosphorylated and translocated into the nucleus allowing the activation of the expression/activity of its target antioxidant proteins, including NAD(P)H dehydrogenase quinone‐1 (NQO‐1), haem‐oxygenase‐1 (HO‐1) and superoxide dismutase (SOD) . Nicolas Papon: Writing‐review & editing (lead).


Toxic Epidermal Necrolysis/Steven–Johnson Syndrome (TEN/SJS) is one of the most serious dermatological adverse reactions triggered mainly by drugs and less likely by infections. COVID‐19 disease is caused by Sever Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) with a wide range of clinical manifestations. Skin involvement is common in COVID‐19 patients including urticaria, purpura, and vasculitis. There were reported cases of TEN/SJS in adults with COVID‐19 infections and only two reported cases in pediatric patients. The causality relationship between COVID‐19 infection and TEN/SJS was not established in most cases due to history of drug usage that could be the trigger. In this study, we are reporting a case of previously healthy child apart from COVID‐19 infection who was admitted to the intensive care unit with TEN involving more than 30% of body surface area confirmed by skin biopsy. The child was treated with intravenous immunoglobulins, steroids, and cyclosporin with a very good outcome. Whether COVID‐19 infection can trigger TEN in pediatrics patient is an important question that needs larger studies, yet it is worth reporting this case of possible correlation between COVID‐19 and TEN in pediatrics. He was tested for COVID‐19 infection as a screening due to contact with positive family member 2 weeks prior to this presentation and had mild symptoms treated supportively at home. He had a history of Ibuprofen use 2 weeks prior to presentation. He was admitted to the hospital for supportive care. During his hospitalization, he had low grade fever and was hemodynamically stable. His skin rash was progressing to violaceous targetoid lesions on the trunk and extremities with genital erosion, Nickolsky sign was positive (Figure 3This report presented a case of a child with TEN and history of recent COVID‐19 infection. Most cases of TEN/SJS are triggered by drugs mainly sulfonamides and anticonvulsants. It usually occurs 4–28 days after drug exposure, delineating the importance of obtaining a detailed drug exposure history.There were case reports of TEN/SJS associated with COVID‐19 infection in adults with probable association with drugs such as hydroxychloroquine,The authors have no conflict of interest to disclose.Lamia Jouhar involved in literature review, writing the manuscript, and obtaining the consent. Marva Yahya and Sohair Elsiddiq involved in reviewing the manuscript.Informed consent was obtained from the parents. The case was approved by the Institutional Review Board at Hamad Medical Corporation.Written informed consent was obtained from the parents.