The impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear.In the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications.In simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09  greater weight-for-age gain per month’s supplement use; this reduced to +0.03  including the interaction.This study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures. Ready-to-use therapeutic food, such as plumpy’nut , is an energy-dense, peanut-based paste containing sugar, vegetable fat and skimmed milk powder, fortified with vitamins and minerals. It was designed, and is widely used, for nutritional rehabilitation of children with severe acute malnutrition. It is also widely used in stunted/wasted HIV-infected children entering antiretroviral therapy (ART) programmes , under tARROW was a randomised controlled trial investigating the impact of different management strategies in HIV-infected children starting ART in Uganda and Zimbabwe (ISCRTN 24791884) –8. In thMarginal structural models (MSMs) with inverse probability of treatment weighting (IPTW) are an established causal inference method to address time-dependent confounding , specifiHowever, with repeated measures data, the underlying outcome trajectory (i.e. the trajectory in the absence of intervention) may depend on its starting value; that is, the intercept and slope may be correlated. For example, independent of supplement use, weight gain after ART initiation is likely accelerated in children who are initially very underweight due to their HIV infection, enabling them to “catch-up” at a faster rate than children only slightly underweight when they start ART.Both the treatment model and the MSM must be correctly specified for unbiased causal inference from IPTW MSMs. Under randomisation, omitting a true correlation between intercept and slope from the MSM would not affect the treatment effect estimate. From the existing literature –12, the Here, we estimate the causal effect of nutritional supplementation on weight gain in HIV-infected children in their first year on ART, and investigate, using empirical observational data and simulation, the impact of incorrectly specifying correlated slope and intercept on estimated treatment effects from IPTW GEEs.ARROW methods and results have been reported previously . In brieAt enrolment (ART initiation) and at 4-weekly follow-up visits, data were collected on clinical and laboratory measures, including weight , height and middle-upper-arm-circumference (MUAC). MUAC and calculated weight-for-height are both used to identify malnutrition. HIV-infected children are often both stunted and wasted so have more normal weight-for-height and therefore weight-for-age is also used when assessing malnutrition. Children considered to have malnutrition at any visit could be supplied with the protein-based supplement “plumpy’nut” at standard doses at the clinician’s discretion, provided this was available through routine sources . In Zimbabwe, children were referred to national malnutrition programmes for plumpy’nut. This analysis was therefore restricted to the three Ugandan study sites , Paediatric Infectious Diseases Clinic (PIDC)) that provided the supplement through the ARROW clinic and therefore recorded all use consistently. Analysis included only children enrolled after December 2007, when supplement use was added to case record forms. Finally, only children under 6 years at enrolment were included, as only 1/98 Ugandan children over 6 years were ever given plumpy’nut. Including older children would lead to large IPTW due to positivity assumption violation  which may bias the causal estimate [Data were organised into 4-weekly intervals, corresponding to scheduled visits. Few scheduled visits were missed (6%) and therefore missing values for covariates and plumpy’nut use were imputed by carrying the most recent observation forward when fitting the weighting models and calculating cumulative plumpy’nut use.th, 50th and 75th percentiles. All baseline covariates and time were used to calculate numerators for the stabilised weights [Due to positivity violations, it was not possible to model binary on/off treatment in each 4 weekly period. As such, weight estimation required the exposure process to be coarsened. The IPTW were calculated by first estimating the probability of initiating plumpy’nut in each monthly interval in those who had not yet initiated (“initiation model”), estimated using logistic regression. Baseline predictors of weight-for-age trajectory included in the initiation model were age, gender, CD4%, WHO stage, primary carer, weight-for-age (z-score), and a combined MUAC/weight-for-height indicator for malnutrition ; used when children were enrolled during 2007–2008). Time-dependent predictors were CD4%, previous weight-for-age, hospitalisation since last visit and MUAC/weight-for-height malnutrition indicator. Weight-for-age and weight-for-height z scores were calculated using WHO references [ weights . These wThese initiation weights effectively assume a treatment probability of one for all visits after plumpy’nut is first started . As durations of plumpy’nut use varied  was estimated using an IPTW GEE  with an The algebraic specification of all weights and the MSM are provided in Our focus was on estimating the treatment effect and, in particular, the bias associated with different analysis methods, rather than variance, which is important for ultimate inference but less so the greater the bias. We therefore simulated a single sample of 200,000 children, with normally distributed baseline weight-for-age z-scores . Simulation parameters for weight-for-age were chosen so that simulated data approximated ARROW data. Weight-for-age at monthly follow-up visits through 1 year was simulated to depend only on the previous weight-for-age and time, with no effect of supplement use, based on the observed mean change per month (0.1 z score increase per month). Supplement initiation was simulated to depend upon current weight-for-age and baseline weight-for-age. Stopping supplement was simulated to depend on current weight-for-age only Eqs . SimulatThe dependence between baseline weight-for-age and underlying weight gain  was then varied to assess its impact on the bias of the estimator of the causal effect of supplement use. This included a scenario where there was no dependence. This was done firstly by adding an interaction term into the underlying model, and secondly by drawing random intercepts (baseline) and slopes from a bivariate normal distribution  based on the estimated SD of the slope in ARROW data). In sensitivity analyses, we repeated the simulations with varying effects of supplementation on weight gain.Once the simulated data were obtained, we fitted the weighting models using the correct model specification, and then applied the estimated weights to the repeated measures MSM using generalised estimating equations as in the application. Two models were fitted to all simulation scenarios. In both, weight for age was the outcome, and plumpy’nut use, baseline weight for age, and time were fitted as main effects. An interaction between baseline weight for age and time was only included in the second model. As such, the estimator of interest in all simulation scenarios, including true randomisation of treatment, was the average treatment effect of plumpy’nut conditional on baseline weight-for-age and time.Main simulation: (1) Treatment allocation and (2) stopping dependent upon baseline and/or current weight-for-age. Control simulation: (3) Treatment allocated under sequential randomisation and stopping (4) dependent upon duration of use onlyWij to be the random variable for weight-for age for subject i at time j, with W0 therefore defined as the baseline weight-for age, and define wij to be the observed weight-for age for subject i at time j. Let Aij be random variable representing treatment for subject i at time j, where A takes the value 0 or 1 to represent the presence of absence of nutritional supplements respectively. Then the data were simulated using parameters which reflected the data observed in the ARROW trial as follows, assuming an underlying weight-for-age increase of 0.1 units per month:Define Fixed effect model with interaction:x = 0, -0.05, -0.1, or -0.2 is the magnitude of the interaction between baseline weight and time, and γ = 0, 0.1, 0.2 or 0.3 is the treatment effect per month extra of supplement use.Random slope simulation modelFor both a) and b):OrFour GEEs (with independent working correlation matrix) were then fitted to investigate biases in estimating the effect of plumpy’nut on weight gain.Model-1: Unweighted GEE adjusting for visit and baseline weight-for-ageModel-2: Unweighted GEE adjusting for visit, baseline weight-for-age and their interactionModel-3 IPTW (MSM) estimated via GEE, excluding an interaction term between baseline weight-for-age and visit in the MSM.Model-4: IPTW (MSM) estimated via GEE including an interaction term between baseline weight-for-age and visit in the MSM.All analyses were conducted using Stata version 14 .The ARROW trial data used for this analysis are provided in 385 Ugandan children were enrolled in ARROW during the study period. 98 were excluded as they were ≥6 years at enrolment, and 4 because they did not have baseline MUAC recorded. Of the 283 children included in the analysis, 63 (22%) initiated plumpy’nut before 12 months on ART, although one initiated it at the 12-month visit. As anticipated, children receiving plumpy’nut were younger, more malnourished and had more advanced HIV disease . Fig 2 p–S5 Tables in Distributions of the stabilised initiation, stopping, and combined weights are shown in Simulation results were similar under both fixed and random effect simulation scenarios . SimulatUnweighted GEEs all showed very large negative bias, demonstrating the key impact of not adjusting for time-dependent confounding . HoweverAssociation between baseline weight-for-age and slope simulated by a bivariate normal distribution (top) and a fixed effect interaction (bottom). Unweighted no interaction: GEE adjusting for time and baseline weight-for-age .To our knowledge, this is the first study to specifically address the implications of dependence between intercept and slope in repeated measures data for correctly estimating causal effects in IPTW MSMs, and the first to estimate the effect of nutritional supplementation on weight gain in HIV-infected children using these causal methods. A previous study used a random effects model with random slope and intercept in a different dataset . The autTo further assess consistency with this previous study, we also fitted an unweighted mixed effects model, allowing random slopes and random intercepts. This suggested much larger beneficial effects of plumpy’nut on weight gain, with a 0.13  increase in weight-for-age per months’ additional plumpy’nut assuming independent intercept and slope, and 0.12  allowing correlation between them. Although in the opposite direction of the expected time-dependent confounding in this context, these results are similar to those obtained from an unweighted GEE using an exchangeable working correlation matrix with no interaction in our study ); which reduced to 0.06  with interaction. We used an independent working correlation matrix in our analyses because exchangeable correlation structures in GEEs may give biased estimates when past outcome affects future exposure as here . It is pBoth our simulation study and data analysis have limitations. Using a single large sample for the simulation study avoids small sample bias, but means we did not investigate precision or variance estimation/coverage. However, our main interest was investigating bias , and the trends in the magnitude of the bias observed with increasing association between baseline and trajectory are still of interest even in the absence of information on precision. The simulation could have included other time-varying confounders  or baseline confounders  of the association between plumpy’nut use and weight-for-age. This may have produced differences between models of more similar magnitude to those in our real-world application, though the bias in the simpler simulation is still demonstrated.Strengths include high quality trial data with little missingness. Therefore, important potential confounders (both baseline and time-varying) were available to fit well-specified models for treatment initiation and outcome. However, data were insufficient to model treatment stopping flexibly, and we could only model continuing vs stopping after 1 month, and assume a fixed average duration of use in everyone that continued. Actual duration is likely informative in terms of weight-for-age gain, meaning some residual time-dependent confounding may remain. However sensitivity analyses assuming different durations of use gave similar conclusions clinically and statistically. The choice to impute missing visits in the weighting models using last observation carried forward was a pragmatic decision based on low numbers of missing visits and the already complex treatment process requiring the combination of two weighting models. Given that only 6% of visits were missed, it is unlikely that a substantial bias was introduced into the weights by using this approach. Use of additional weights for censoring or missingness may be useful to explore in further research as an alternative approach.Other factors may also have been useful to further control for confounding in both initiation and stopping models, such as food insecurity, overall calorie intake or types of food available. Additionally, in one site, the baseline indicator for having low MUAC or height-for-age perfectly predicted treatment initiation, leading to a strict violation of the positivity assumption, and meaning this predictor could not be included in this initiation weighting model. However, it is unlikely that any serious residual time-dependent confounding remains due to its omission since, as a baseline variable, it was still included in the MSM. Lastly, also to avoid strict positivity violations, children aged 6 year or older at ART initiation were excluded from the analysis; our results are therefore generalizable only to children under 6 years.The final MSM was considered to be the best possible parsimonious model, but it should be acknowledged that there may have been some remaining mis-specification, since tests for other interaction were based on Wald tests that may have been underpowered. Additionally, the difference between the standard and IPTW analyses in the empirical example were relatively small in magnitude. This could be because most children receiving the supplement initiated it in the first 3 months, and so the effect of post-baseline confounding was not as strong as initially hypothesised. The models with and without interactions between baseline weight-for-age and time produced what could be clinically relevant differences in the point estimates of the benefits of plumpy’nut, which are not explained by any of the limitations above. Due to some overlap in confidence intervals, random variation cannot be ruled out. However, the supporting simulation study identifies a clear problem from model misspecification when baseline and trajectories are associated and interactions are not included in the MSM.For true causal interpretation, the underlying assumptions of conditional exchangeability, consistency, no interference and positivity are required to hold .AdditionOur findings suggest that HIV-infected children initiating ART with low weight-for-age have no additional weight gain due to nutritional supplementation. This contrasts prior studies suggesting benefits of nutritional supplementation but without adjusting for time-varying confounders . Our datIn summary, correct specification of both the IPTW and MSM models is a necessary assumption for causal interpretation of the resulting estimate. This study highlights a specific situation in which MSM model misspecification may occur and have an impact on the resulting estimate. Due to such misspecification being irrelevant under true randomisation, the importance of accounting for correlated slope and intercept may not be immediately obvious to those using MSMs for repeated measures. Additional simulation studies that assess more complex model specifications, variance, mean square error and coverage are required to provide concrete recommendations, but our initial findings suggest that since an interaction in the MSM (outcome) model does not appear to bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(XLSX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.S5 Appendix(XLSX)Click here for additional data file.S6 Appendix(DOCX)Click here for additional data file.


The novel Coronavirus disease-19 (COVID-19) pandemic has posed several challenges for neuromuscular disorder (NMD) patients. The risk of a severe course of SARS-CoV-2 infection is increased in all but the mildest forms of NMDs. High-risk conditions include reduced airway clearance due to oropharyngeal weakness and risk of worsening with fever, fasting or infection Isolation requirements may have an impact on treatment regimens administered in hospital settings, such as nusinersen, glucosidase alfa, intravenous immunoglobulin, and rituximab infusions. In addition, specific drugs for SARS-CoV2 infection under investigation impair neuromuscular function significantly; chloroquine and azithromycin are not recommended in myasthenia gravis without available ventilatory support and prolonged prone positioning may influence options for treatment. Other therapeutics may affect specific NMDs  and experimental approaches for Coronavirus disease 2019 may be offered “compassionately” only after consulting the patient’s NMD specialist. In parallel, the reorganization of hospital and outpatient services may change the management of non-infected NMD patients and their caregivers, favouring at-distance approaches. However, the literature on the validation of telehealth in this subgroup of patients is scant. Thus, as the first wave of the pandemic is progressing, clinicians and researchers should address these crucial open issues to ensure adequate caring for NMD patients. This manuscript summarizes available evidence so far and provides guidance for both general neurologists and NMD specialists dealing with NMD patients in the time of COVID-19. Symptomatic SARS-CoV-2 infection causes a wide spectrum of symptoms , such as fever, dry cough, and fatigue in milder cases and systemic manifestations in severe disease courses  pandemic has claimed the lives of more than 400,000 individuals worldwide  present an increased risk due to their impossibility to isolate .Following available guidelines, and in the opinion of the authors, NMD patients who do not present a high or very high risk of severe complications should follow general rules outlined in the World Muscle Society (WMS) guidelines . ConversThe SARS-CoV-2 pandemic has forced a quick reorganization of hospital facilities and outpatient services to address new patients’ needs. Local differences in response have depended mainly upon geographical localization of hospitals, patient population, distribution of sick patients, and the overall organization of the health care system , 13. In During the first days after the virus spread in our area, the need for intensive and sub intensive care beds in hospitals selected as “COVID Hubs” (appointed by the authorities), the shortage of PPE and the increased infection risk for patients imposed consistent changes in the management of our NMD patients. Elective or “non-urgent” patient visits were postponed to avoid unnecessary exposure for patients and clinical staff, favouring virtual encounters. Other services, such as electrodiagnostic tests, muscle, and nerve biopsies, were suspended unless urgent cases required further evaluations . Ancillary services needed reorganization of personnel and resources: pulmonary assessments were stopped due to increased risk of viral shedding from tested patients; tests for dysphagia were performed for cases at increased risks of complications or unplanned hospitalizations; speech therapy and neuropsychological evaluations, whenever possible, were conducted on virtual platforms.https://www.esmo.org/for-patients/patient-guides/cancer-care-during-the-covid-19-pandemic)  Tables . NMD pat) Tables ” section) Tables ” sectionAn initiative that may help neuromuscular centres to reorganize patient care is the use of quality-of-life surveys sent to NMD patients to follow up on their feelings and needs and consequently modulate appropriate responses, as already assessed in immunocompromised patients . In paraThe pandemic has prompted a reorganization of rehabilitation services as well. Rehabilitation patients’ admission has been reduced in different countries to sustain increased hospital bed capacity and home-based rehabilitation services have been suspended or offered at-distance . Alternan = 4) of patients with facioscapulohumeral muscular dystrophy suggested that this approach is considered acceptable by patients and it correlates with a reduction of hospital admission [Overall, three unblinded studies on the use of teleneurology in ALS patients reported satisfaction among patients, caregivers, and health-care providers –26. Two dmission . In anotdmission . Other sdmission . Considedmission . A simildmission .https://www.aan.com/siteassets/home-page/tools-and-resources/practicing-neurologist--administrators/telemedicine-andremote-care/20-telemedicine-and-covid19-v103.pdf) [During the pandemic, the need for prevention and mitigation strategies has moved telemedicine towards the front lines of clinical practice. Professional societies are sharing guidelines on the correct implementation of telehealth approaches for neurological patients (e.g. 103.pdf)  and repo103.pdf) . The use103.pdf) . Disease103.pdf) .AltogethDifferent expert panels  and inteSeveral NMDs recognise immune-mediated pathogenesis. The extent to which immunosuppressive drugs can contribute to severe forms of SARS-CoV-2 infection is still unclear. Depending on the regional pandemic burden, patient compliance, and caregivers’ support, NMD specialists may want to consider a reduction of the dose of some immunosuppressive drugs or shift to less immunosuppressive alternatives for high-risk patients . This deCurrently, no evidence suggests that immunoglobulin therapy (intravenous or subcutaneous), plasma exchange, or Fc receptor antagonists )  may incrImmunomodulant therapies currently used in NMD patients may help against SARS-CoV-2 infection. Some severe SARS-CoV-2 cases with acute respiratory insufficiency may be associated with complex immune dysregulation and excessive activation of inflammatory pathways . At the An adequate provision of drugs represents another key issue for NMD patients. Frequent visits to pharmacies may expose them to unnecessary risk. However, during the pandemic, many pharmacies have expanded their services, waiving fees for home-delivery, and extending refill periods .Clinical syndromes associated with SARS-CoV-2 infection have been classified by the World Health Organization (WHO) as uncomplicated disease, mild pneumonia, severe pneumonia, acute respiratory distress syndrome (ARDS), sepsis, and septic shock . In caseInpatient admission should be avoided when possible, but it should not be delayed if necessary . Indeed,Patients, caregivers, and their physicians and neurologists should bear in mind that, in an emergency setting, such as during the SARS-CoV-2 pandemic, hospitals may have to apply a ceiling of care based on age and pre-existing conditions –45. In aConditions with a good prognosis for recovery include autoimmune and congenital myasthenia, metabolic myopathies, inflammatory myopathies without severe systemic damage , muscle channelopathies, and most neuropathies, hereditary or acquired . The posNeuromuscular pathologies with slight progressionRespiratory functions being minimally impaired and stabilizedMild and stabilized heart diseaseAbsence of severe thoracic deformities/severe contractures preventing ventral decubitusAbsence of multisystemic impairment and comorbiditiesPreservation of autonomy for everyday life acts and/or social environment to supplement daily life tasks For other patients, the criteria in favor of resuscitation/ICU admission are :NeuromusSimilarly, patients with end-stage or incurable diseases should be encouraged to discuss with their loved ones their wishes regarding resuscitation and intubation, and, if necessary, to write them down beforehand.Limited literature exists on the clinical course and recovery of NMD patients with SARS-CoV-2 infection. A small case series of 5 immunosuppressed MG patients showed high variability of disease severity and outcome . Three o2WHO recommends that all patients with SARS-CoV-2 severe acute respiratory infection (SARI) are started immediately with supplemental oxygen therapy at 5 L/min and that flow rates are titrated to reach target SpOnt}≥ 90% . However2) to fraction of inspired oxygen (FIO2) ratio on ICU admission spanned from 136 to 169 [Hypercapnia is not a classic feature of SARS-CoV-2 pneumonia, and its appearance might signal the onset of respiratory muscle weakness . Further6 to 169 –50, very6 to 169 , 42% . Remdesivir is a novel nucleotide analogue developed for the treatment of Ebola and Marburg viruses. Remdesivir was shown to have in vitro antiviral activity against SARS-CoV-2 in vitro [www.clinicaltrials.gov). Azithromycin is a macrolide antibiotic that may be able to suppress inflammation [www.clinicaltrials.gov), although published reports so far are scarce and anecdotal [Chloroquine (CQ) and its less toxic derivative, hydroxychloroquine (HCQ), have been developed as antimalarial drugs; nowadays, they are used also for chronic rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (AR). These drugs also show antiviral activity , and recin vitro  and, in in vitro . Howeverin vitro . Furtherammation  and be eammation . It is nammation , 61. Tocammation . For thinecdotal , 82. Ecunecdotal . Notablynecdotal , 84.The most dangerous complication that may arise during short-term treatment with such agents is QTc prolongation and arrhythmias , 63. In Treating the underlying NMD disease in SARS-CoV-2 patients may be challenging. One report describes the therapy of an MG exacerbation presenting with dysphagia, neck weakness, and diplopia during the infection. Anand et al.  administOverall, the literature on NMD patients with SARS-CoV-2 infection is limited in number and general considerations are difficult. Best management for MG patients with SARS-CoV-2 may represent a dilemma and the use of large registries may prove helpful to improve care for this patient population.In this work, we have reviewed the existing literature regarding the management of NMD patients with and without SARS-CoV-2 infection, addressing the concerns and challenges on the recommendations on disease-modifying therapies, the use of oxygen and ventilatory support, the contraindications and complications of drugs used in COVID-19 patients, and the implementation of telehealth approaches for NMD patients. Besides, we have shared our experience from Lombardy, one of the SARS-CoV-2 worst-hit areas worldwide, our thoughts on the role of NMD specialists in the pandemic and our view on the current and future role of NMD centres, hoping to help the Neurological community in this common effort against the coronavirus.Different reports on SARS-CoV-2 impact on neurologic patients have been published in different countries with unprecedented speed and collaboration among centres, but several questions regarding NMD patients remain unanswered. Given the possibility of subsequent waves of the pandemic, we will need a robust reorganization of neuromuscular centres, where the role of telemedicine will be prominent. We will have to stay vigilant on COVID-19 infection- and COVID-19 therapy-related NMD complications, patients with pre-existing NM diseases and new drugs that may worsen specific NMD conditions.Finally, a strong collaboration among centres and institutions in the Neurology community will be fundamental and will provide the data to help patients with NM disorders; sharing near real-time information, using virtual communication platforms, receiving constant follow-ups from patients in the form of online surveys and updating uniform national and international guidelines may prove valuable in the mid-term period.Now more than ever, the old saying holds: “no man is an island”.All data generated or analysed during this study are included in this published article (and its supplementary information files).


Obesity in adolescents with chronic fatigue syndrome: an observational study. Arch Dis Child 2017;102:35–9. doi: 10.1136/archdischild-2016-311293.Norris T, Hawton K, Hamilton-Shield J, The Editor of the journal has agreed to the request from the authors that the ethics statement should be changed to improve its clarity. The new statement is as follows: ‘The CFS/ME patient data used in this study were collected as part of routine clinical practice and anonymised for the National Outcomes Database. Under the Governance Arrangements for Research Ethics Committees (September 2011), ethical review is not required for research limited to the use of previously collected, non-identifiable patient information.’


EIT RawMaterials, initiated and funded by the EIT (European Institute of Innovation and Technology), a body of the European Union, is the largest consortium in the raw materials sector worldwide. Its vision is to develop raw materials into a major strength for Europe. Its mission is to enable sustainable competitiveness of the European minerals, metals, and materials sector along the value chain by driving innovation, education, and entrepreneurship.EIT RawMaterials unites more than 120 core and associate partners and 180+ project partners from leading industries, universities, and research institutions from more than 20 EU countries. Partners of EIT RawMaterials are active across the entire raw materials value chain, from exploration, mining, and mineral processing to substitution, recycling, and circular economy. They collaborate on finding new, innovative solutions to secure the supplies and improve the raw materials sector in Europe.Two successful projects in the Nordic countries are NITREM, where scientist and industry have developed new technology for removing nitrogen, and MULSEDRO, where the consortium has created a unique multi-sensor drone system for fast and inexpensive mineral exploration.Nitrogen impacts on the environment from mining operations are reduced through bioreactor technology in combination with a geomorphic landscape designwww.nitrem.eu) supported by EIT RawMaterials . The technology development has been driven by EU’s Water Framework Directive and will enable the industry to meet current and future discharge requirements. The outcome is a low-cost and low-maintenance technology ready for market introduction and customer testing.An effective method to purify water leaking from mine waste deposits from nitrogen has been developed in the innovation project NITREM (https://www.lkab.com/en/about-lkab/from-mine-to-port/mining/) in northern Sweden, and is currently being tested in a full-scale operation at the same mine. The Kiruna mine is the largest and most modern underground iron ore mine in the world.The bioreactor technology was previously evaluated in a pilot-scale system at EIT RawMaterials partner LKAB’s Kiruna mine .In another successful project, supported by EIT RawMaterials, the project members have developed a multi-sensor drone system for fast and inexpensive surveying for mineral exploration. This fixed-wing drone system is a fruitful result of the project MULSEDRO: Multi-sensor drones for geology mapping (https://radai.fi/2020/10/16/mulsedro-project/) has, together with other partners in this upscaling project, developed an automated system that can cover large areas in a short time. The multi-sensor drone system has proven to give reliable results under Finish winter conditions and in mountainous and arctic regions such as Greenland (https://www.isaaffik.org/mulsedro-multi-sensor-drones).The Finish company Radai Ltd. , EIT RawMaterials supports Radai Ltd. with Booster funding to accelerate business in the post-crisis economy. The EIT RawMaterials Booster Call in response to the COVID-19 crisis mobilised EUR 9.8 million to provide targeted support to 60 high-impact and growth potential start-ups, scale-ups, and SMEs during the crisis.As part of the EIT Crisis Response Initiative  and Denmark and Greenland (GEUS), the German Helmholtz-Institute for Resource Technology (HZDR-HIF), the exploration technology developing company DMT GmbH & Co. KG, and the business developer LTU Business AB.


BMI was neither associated with cf-PWV nor with cr-PWV values but was a strong predictor of LVMI (<0.001), whereas cardiac mass and BP z-scores were not related. Conclusions: Our study suggests that, in children, elevated BP values and excess weight may have different effects on the heart and the vessels in causing early cardiovascular alterations.Background: High blood pressure (BP) and excess weight can lead to early cardiovascular organ damage already in children. Carotid-femoral pulse wave velocity (cf-PWV) is the non-invasive gold standard method for assessing aortic stiffness, while carotid-radial PWV (cr-PWV) provides information on the distensibility of the upper limb arteries. The aim of this study was to evaluate the relationship of BP and BMI z-scores with arterial stiffness and left ventricular mass index (LVMI) in a pediatric population. Methods: In 343 children , systolic (SBP) and diastolic (DBP) BP, BMI, cf-PWV, cr-PWV and LVMI were measured. A multiple linear regression model was used to assess the impact of BMI and SBP (or DBP) z-scores on cf-PWV, cr-PWV and LVMI. Results: About 21% of children were normal weight, 34% were overweight and 45% obese. Adjusted for possible confounders, SBP and DBP z-scores were significantly associated with cf-PWV ( The aorta and large elastic arteries play a fundamental role in the hemodynamics of the cardiovascular system. During the systolic phase of the cardiac cycle, thanks to their viscoelastic properties, the large arteries have an important buffer function on the left ventricular ejection. The potential energy stored in systole in the aortic wall is transformed into kinetic energy during the diastolic phase of the cardiac cycle (the Windkessel effect), performing an essential propulsive function . AlteratSeveral studies showed a positive association between cf-PWV and arterial BP values in children ,8,9,10. The aim of this study is to evaluate the relationship between BP and BMI z-scores and arterial stiffness, evaluated by measurement of cf-PWV and cr-PWV, in children. Furthermore, we also evaluated the relationship between BMI z-scores/body weight class and BP z-scores/BP category with left ventricular mass index (LVMI), to assess if different cardiovascular risk factors have different effect on early organ damage in childhood.A cohort of children and adolescents consecutively referred to the Pediatric Center for Cardiovascular Risk Prevention of the Istituto Auxologico Italiano in Milan, from October 2013 to December 2018 was recruited. Exclusion criteria were age less than 5 or more than 18 years, secondary forms of hypertension, congenital cardiovascular diseases, history of aortic surgery, arrhythmias, impaired glucose tolerance, diabetes and renal insufficiency. Patients underwent a clinical evaluation, transthoracic echocardiography and arterial tonometry on the same day. Anthropometric parameters and clinical history were collected during the clinic visit. The study protocol was approved by the local institutional ethics committee and conformed to the ethical guidelines of the 1975 Declaration of Helsinki . Informed consent was obtained from parents or legal representatives before the enrollment in the study.2), and weight class was defined according to the International Obesity Task Force classification, distinguishing among normal weight, overweight, and obese classes [BMI was calculated as weight/height (kg/m classes . BMI z-s classes . The wai classes  to class2.7) [Two-dimensional M-mode, pulsed-wave Doppler and tissue Doppler echocardiography analyses were obtained in the standard precordial positions using digital echocardiography equipment , with 1–5 MHz transducers and following the recommendations for standard M-mode measurements. Instantaneous measurements were made over three cardiac cycles and the average values were obtained from each patient for the following parameters: left atrial end-diastolic diameter (LAd), interventricular septum thickness at end diastole (IVSd), left ventricular posterior wall thickness at end diastole (LVPWd) and left ventricular end-diastolic diameter (LVEDd). Left ventricular mass (LVM) was calculated according to the American Society of Echocardiography convention and indexed (LVMI) to height (m2.7) . Left ve2.7) .Measurements were obtained after 10 min of rest and at a stable room temperature. A validated, easy-to-use and high-fidelity PulsePen tonometer  was used in this study ,26. Repr2 and z-score values) were represented in scatterplots with Pearson correlation statistics. A multiple linear regression model was used to assess the impact of age, gender, heart rate, BMI and SBP (or DBP) on the cf-PWV and on the cr-PWV and the impact of age, gender, BMI and SBP (or DBP) on the LVMI. All the analyses were conducted with the package R [The sample was categorized according to weight class and BP category. The continuous variables were described by mean and standard deviation (SD) and the distributions were compared across groups by one-way analyses of variance with α = 0.05 significance level. Post hoc pairwise comparisons were obtained according to the Bonferroni correction significance level (α/3). The categorical variables were described by the proportion of subjects falling into each category. Proportions were compared across groups by the Chi-Square test with post hoc pairwise comparisons obtained according to the Bonferroni correction significance level (α/3). The univariate association between cf-PWV (cr-PWV) and SBP , DBP , mean BP (MBP) and heart rate were represented in scatterplots, where a 95% confidence interval on the Pearson correlation test and the p-value were displayed. Similarly, the associations between LVMI and SBP  and DBP  and BMI  were enrolled in the study. p < 0.02). SBP and DBP z-scores increased significantly as the weight class worsened (p < 0.001 in both cases). LVMI values were significantly greater in overweight and obese compared to normal weight children (p < 0.02 in both cases), while the highest prevalence of left ventricular hypertrophy was in obese children (p < 0.02). There were no differences in cf-PWV and cr-PWV values according to weight class , whereas BMI z-score and waist-to-height ratio increased from normotensive to children with more elevated BP values (p < 0.02). Cf-PWV values were significantly increased in higher BP categories compared to normotensive children (p < 0.02 in both cases). Cr-PWV values were significantly higher in high normal (BP) subjects compared to normotensives (p < 0.02). There were no differences in LVMI among the BP categories .At univariate analysis, cf-PWV  and cr-Pp < 0.01, p < 0.05, Multiple linear regression models showed that age, heart rate, SBP and DBP z-scores were significantly associated with cf-PWV , while the relationship between cardiac mass and SBP z-scores disappeared.From the multiple linear regression model in p = 0.008), while overweight and obesity were associated with increased values of LVMI . Heart rate was shown to be significantly associated with both cf-PWV and cr-PWV . If body weight was included in the multivariate models as central adiposity (waist-to-height expressed as a continuous variable or as waist-to-height ratio >50%) results did not change significantly.When body weight and BP were included as categorical variables (weight class and BP category), multiple regression analysis showed that the presence of hypertension was strongly associated with increased values of cf-PWV  indexed values of SBP and DBP, i.e., z-scores, are strongly associated with cf-PWV values in a pediatric population; (ii) SBP z-score is not a predictor of cr-PWV values, while heart rate and DBP z-score are significantly related with cr-PWV; (iii) BMI z-score is a strong predictor of LVMI, while there is no relationship between BMI z-score and cf-PWV and cr-PWV values.Our study demonstrates a relationship between the indexed values of SBP and DBP  and PWV. Several studies showed higher PWV values in hypertensive than normotensive children and adolescents ,8,9,10. In our population, a relationship between SBP z-scores and PWV was present only for cf-PWV, and not for cr-PWV, which in turn was significantly associated with DBP z-scores and heart rate values only. While cf-PWV is a reliable index of viscoelastic properties of the aorta and large elastic arteries, cr-PWV assesses the mechanical properties of the muscular upper limb arteries. Thus, while the cf-PWV increases above all in the presence of structural alterations of the aortic wall, the aorta being poorly innervated by the sympathetic system, on the other hand, cr-PWV reflects the functional condition of the arterial tree, which is closely related to the activation of the sympathetic system. This explains the close link between cr-PWV and diastolic BP and heart rate. However, it does not mean that the sympathetic system cannot influence the distensibility of the aorta; indeed, the sympathetic nervous system promotes arterial stiffness independent of blood pressure via endothelial dysfunction, growth of vascular muscle and associated fibrosis, by its effects on the renin-angiotensin aldosterone system, promoting arterial wall fibrosis. This influence of the sympathetic system on arterial distensibility occurs both on the aorta as well as on muscular arteries. Moreover, while cf-PWV increases significantly with aging, cr-PWV does not change with age. At present, no study has shown any prognostic or clinical significance of high cr-PWV values.n = 501, n = 141 and n = 227, respectively). On the contrary, Urbina et al. showed an increased arterial stiffness in 195 diabetic adolescents and young adults with obesity compared to 241 lean controls and to 234 non-diabetic obese subjects [n = 27) and obese children (n = 22), Koopman et al. found a positive association between BMI and cf-PWV values, after adjusting for SBP and heart rate [n = 3423), that persistence of high total fat mass during adolescence, assessed using dual-energy x-ray absorptiometry (DEXA), was positively associated with increased cf-PWV. This adverse association was absent with BMI or waist-to-height ratio [The results of our study suggest the absence of any association between BMI and PWV, after correction for possible confounding factors. Other studies report contradictory results on the relationship between BMI and arterial stiffness. Lurbe et al. , Hvidt esubjects . In a piart rate . More ren = 526), we demonstrated that BP z-score and BMI z-score both play a role in influencing LVMI values. However, while BP retained its independent predictive value, the role of BMI in determining the increase of LVMI and of the presence of left ventricular hypertrophy was much greater [A completely new finding of our study is that high BP values and excess weight exert a different effect on arterial distensibility and on cardiac mass, causing early differentiated damage to target organs. In a previous study, performed in a larger number of subjects ( greater . MoreoveThe main limitation of the study is the observational approach that does not allow us to assess the causal association between BP values and aortic distensibility, evaluated by measurement of the cf-PWV. These two parameters likely influence each other, and more studies are needed to understand how aortic stiffening affects BP and how an increase in BP affects PWV in children. Another limitation of the study is that total fat mass was not measured. In our research, only BMI, waist circumference and waist-to-height ratio were considered. In a similar population, Dangardt’s study  showed aIn conclusion, this study showed a strong association between BP z-scores and cf-PWV values, and a significant association between BMI z-score and LVMI. No association was found between the BMI z-score and cf-PWV values. Our study suggests that already in the pediatric age there is a close relationship between high blood pressure and vascular stiffness and that the impact of high blood pressure and weight excess is different if we consider two different indices of early organ damage. Only prospective studies will be able to demonstrate whether the described relationship of hypertension and weight excess with early organ damage in children may constitute a real cardiovascular risk factor in the future adult as well.


With the increasing emphasis on environmental protection, the development of flame retardants for epoxy resin (EP) has tended to be non-toxic, efficient, multifunctional and systematic. Currently reported flame retardants have been capable of providing flame retardancy, heat resistance and thermal stability to EP. However, many aspects still need to be further improved. This paper reviews the development of EPs in halogen-free flame retardants, focusing on phosphorus flame retardants, carbon-based materials, silicon flame retardants, inorganic nanofillers, and metal-containing compounds. These flame retardants can be used on their own or in combination to achieve the desired results. The effects of these flame retardants on the thermal stability and flame retardancy of EPs were discussed. Despite the great progress on flame retardants for EP in recent years, further improvement of EP is needed to obtain numerous eco-friendly high-performance materials. Since the invention of epoxy resin (EP) in the 1930s, significant progress has been achieved in EP which can satisfy different requirements in practical applications. EPs have been widely used as coatings, composite materials, castables, adhesives, molding materials and injection molding materials, owing to the exceptional mechanical properties, dimensional stability, suitable chemical and thermal resistance ,3,4,5,6.To date, numerous works have been done on flame retardants for EPs ,13,14,15Numerous halogenated flame retardants (such as polybrominated diphenyl ethers) have been banned worldwide due to their growing and continuing threat to the environment and organisms . Many haCurrently, research focuses on environmentally friendly flame retardants for EPs include phosphorus-based flame retardants, carbon-based materials, silicon-containing compounds, nanocomposites, and metal-containing compounds. For instance, X. Li  et al. uThis review focuses on recent advances of a few popular flame-retardant systems for EP, including phosphorus flame retardant, carbon-based materials, silicon flame retardants, nanocomposites and metal-containing compounds. The concerns on the practical applications of flame retardants are also involved. It is necessary to ensure that the other properties of the EP are not sacrificed while improving the flame-retardant performance. We believe this review could provide a timely progress report on the flame retardants for EP and benefit junior researchers in this field. Currently, some flame retardants used in EPs have been commercialized. Although halogen-based flame retardants have been opposed by many countries, bromine-based flame retardants still play a significant role in the field of flame retardants. Tetrabromobisphenol A is still the single largest flame retardant in terms of current commercial value. It is widely used in printed circuit boards of FR-4 EP, and is priced as a commodity. In addition, some high-load metal hydroxides were used by some Japanese companies. A Hitachi Chemical  patent sPhosphorus-containing flame retardants are important components of halogen-free flame retardants which possesses excellent properties such as low smoke emission, low toxicity, and formation a stable carbonized layer after burning ,44,45. TFlame retardants based on inorganic phosphorus mainly include red phosphorus, APPs and phosphates. Inorganic phosphorus compounds are halogen-free and non-volatile and have long-lasting flame-retardant effects as well as thermal stability . They arAPP has attracted attention in recent years because of its high decomposition temperature and good thermal stability. However, a surface modification treatment is required due to its poor compatibility with polymers. A novel APP modified with branched polyethyleneimine (PEI) (named as APP-PEI) was synthesized  56]. Th. Th56]. 2O could reduce the toxicity of combustion products due to its catalytic reduction coupling effect  tetramethyldisiloxane (BISE) was synthesized  142]. B. B142]. In order to achieve higher flame retardant effect, siloxanes are often used in combination with other highly efficient flame retardant additives. A series of novel macromolecules containing phosphinophenanthrene/phenylsiloxane bifunctional groups (DDSi-n) were synthesized  and theiSilica is one of the commonly used fillers for modifying EP. The introduction of silica in polymers could promote the formation of carbon layers and improve the oxidation resistance, which not only provides the polymer with flame retardancy, but also improves the polymer’s processability, mechanical properties and heat resistance ,147. TheSpherical silica has aroused great interest due to the advantages of high loading, high fluidity and low thermal expansion coefficient. S.-E. Hou  et al. p2@CS@PCL) was synthesized by coating chitosan (CS)/phosphorylated cellulose (PCL) onto the surface of hollow mesoporous silica (HM-SiO2) (A green multi-element silica derivative (HM-SiOHM-SiO2) , and intg was increased. The EP nanocomposites possessed thermal stability due to the addition of silica, and the presence of GLYMO enhanced the organic compatibility of epoxy nanocomposites, further improving the thermal stability.A. Afzal  et al. s2), used in combination with EPs and subsequently investigated for their flame retardancy and mechanical properties. The results exhibited that the introduction of RH-SiO2 enhanced the flame retardancy and mechanical properties of epoxy composites. With the addition of 20 wt.% RH-SiO2/10 wt.% DOPO-J-ESO, a V-0 rating in the UL-94 test and an LOI value of 35.9% could be achieved, the PHRR was reduced by 46.1% compared to neat EP, and the impact strength was increased by 90.1%. Analysis of the results of the energy-dispersive X-ray spectroscopy (EDS) revealed that the improvement in flame retardancy was due to the carbon layer formed during the combustion process, and the polymer oxygen (PO) and polymer peroxy (POO) radicals formed by the decomposition of DOPO-J-ESO react directly with H and OH to form completed molecules.Three different phosphorus-containing silicas were prepared from di-sodium hydrogen orthophosphate, orthophosphoric acid, hypophosphorous acid and sodium silicate respectively, and added these three compounds to the epoxy composite . The resnO3n/2Rn  . F. F160]. A novel halogen-free flame retardant (ODMAS) containing DOPO and POSS was synthesized , and useA flame-retardant additive (POSS-bisDOPO) containing POSS, DOPO and polyoxymethylene (POM) was synthesized via Kabachnik–Fields reaction and its fire performance tested on EPs . POSS-big of nanocomposites with 2.0 wt.% L-POSS-D was 47.7 °C higher than neat EP. L-POSS-D also improved the impact toughness and flexural strength, which were 157.7% and 22.7% higher than neat EP, respectively. The improvement of the mechanical properties was due to the great interaction between L-POSS-D and EPs and the reduction in the nano-fillers’ volume fraction in composites. G. Liang [g of the composites increased with increasing content of POSS until its content exceeded 10 wt.%. The char residue of EP composite monotonously increased with increasing content of POSS. The increase in carbon residue content was due to the Si-O-Si structure of POSS leading to higher inorganic components and higher residual carbon.In addition, POSS can be grafted and copolymerized with other materials or monomers to improve the thermal stability of the composites at the molecular level . Y. ZhenG. Liang  et al. sThe flame retardant performance of the silicon flame retardants mentioned in the article is shown in In recent years, nanocomposites have been extensively researched and developed ,167. DueIt has been reported that the addition of organically modified montmorillonite (OMMT) to EP could improve the performance of thermal and flame-retardant. W. Yan  et al. mIn addition to MMT, CNTs are also one of the most widely used fillers. The effect of adding fluorinated MMT/MWCNT additives on EP was investigated by Y.-S. Lee  et al. MThe flame-retardant performance of the nanocomposites mentioned in the article is shown in Metal-containing compounds are also one of commonly used flame retardants in practice applications. Especially, metal hydroxides or oxides are the most representative metal-containing compounds, which have the merit of low smoke, low toxicity and low cost ,175. Add2) to research their synergistic flame retardant effect. The experimental results showed that all three flame retardants could impart flame retardancy to EP. MPAlP, MPZnP and MPMgP both worked in the gas phase and the condensed phase, but mainly by increasing the residue and protective layer in the condensed phase. The Tg of all composites exceeded 150 °C. The introduction of MPAlP halved pk-HRR, while MPZnP and MPMgP reduced pk-HRR by more than 70%. In addition, it was found that the combination of MPZnP and MPP had a synergistic effect on improving the flame retardancy.In recent years, metal-containing flame retardants have aroused much interest. Q. Yin  et al. pThe flame retardant performance of the metal-containing compounds mentioned in the article is shown in This paper covers the flame retardants of EP currently available or under serious development. At present, researches on the modification of EPs have made great progress, but with the development of technology, the requirements of EP composites have become higher. Currently, the performance of EP cannot meet the needs of high-tech fields. It is difficult for a single element to meet the requirements of efficient flame retardancy, and much work is still needed to improve the comprehensive performance of EPs. It is necessary to explore the use of new technologies and a combination of multiple synergistic flame-retardant technologies to modify EP.The flame-retardant EP system is a complex system consisting of various components, including flame retardants, carbonization promoters, coupling agents and crosslinking agents, smoke suppressing agents, fillers and the like of different properties. Obviously, such a complex system cannot fully guide its formulation by a few empirical rules and general scientific principles. In order to obtain the optimized overall performance of this system, it is necessary to study the interaction between these components to exert the gain between them and avoid the harmful and mutually offsetting effects between them. Future research directions for EP flame retardants focus on environmentally friendly materials, sustainable materials, multifunctional additives and synergistic flame retardants.


Background: Activation delay in ischemic myocardium has been found to contribute to J-wave appearance and to predict ventricular fibrillation (VF) in experimental myocardial infarction. However, the role of ischemia-related repolarization abnormalities in J-wave generation remains unclear.Objectives: The objective of our study was to assess a contribution of myocardial repolarization changes to J-wave generation in the body surface ECG and VF in a porcine acute myocardial infarction model.Methods: In 22 anesthetized pigs, myocardial ischemia was induced by occlusion of the left anterior descending coronary artery  and right coronary artery . Body surface ECGs were recorded simultaneously with intramyocardial unipolar electrograms led from flexible electrodes positioned across the left ventricular (LV) wall, interventricular septum (IVS), and right ventricular (RV) wall at apical, middle and basal levels of the ventricles . Local activation times (ATs) and activation-repolarization intervals  were measured.Results: J-waves appeared in left precordial leads  and right precordial leads . During ischemic exposure, ATs prolonged, and the activation delay was associated with J-wave development  and VF incidence . ARIs shortened in the ischemic regions . The difference between maximal ARI in normal zones and ARI in the ischemic zones (ΔARI) was associated with J-wave appearance  independently of AT delay in multivariate logistic regression analysis.Conclusions: Both AT delay and increase of ΔARIs contributed to the development of J-wave in body surface ECG. However, only AT delay was associated with VF occurrence. The presence of J-wave in ECG once considered a benign phenomenon  was subsExplanation for J-wave generation remains equivocal. An alternative name for this phenomenon, an early repolarization pattern, suggests an essential role of certain repolarization distinctions in its development. Indeed, in isolated myocardial preparations J-wave was demonstrated to be a manifestation of a transmural potential difference resulting from variation in spike-and-dome morphology of action potentials across the ventricular wall . A numbein vivo model of acute myocardial infarction, we directly demonstrated an association between activation delay in the ischemic myocardium, J-wave, and VF occurrence  characterized by changes in depolarization suggests that there are alternative, including depolarization-related mechanisms of its formation . Myocardcurrence . HoweverThe objective of the present study was to assess an association between myocardial repolarization changes and J-wave appearance in body surface ECG and VF incidence in a porcine acute myocardial infarction model.Guide for the Care and Use of Laboratory Animals, 8th Edition published by the National Academies Press (United States) 2011, the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes and was approved by the Ethical Committee of the Institute of Physiology of the Komi Science Centre, Ural Branch of Russian Academy of Sciences. Experimental procedures were described earlier  purchased from a local producer. The study conformed to the  earlier . Brieflyn = 14) or right coronary artery . Three flexible plunge electrodes  were placed in the anterior portion of the left ventricle (LV), interventricular septum (IVS), and right ventricle (RV) at apical, middle, and basal levels  was assessed by staining with Evans blue dye , which was injected into the coronary arteries with LAD or RCA ligature tightened , panel CIn each intramyocardial lead, local activation time (AT) and end of repolarization time (RT) were measured from the body surface QRS onset to instants of a dV/dt minimum during QRS-complex and dV/dt maximum during T-wave, respectively; activation-repolarization interval (ARI) was calculated as a difference between RT and AT . J wave in vivo we could not utilize classical measurements of action potentials in a way performed by A major challenge of the present study was that in the setting post-hoc test) or nonparametric (Wilcoxon and Fridman tests) were used for repeated measurements. Comparisons between different groups of animals were done with Student’s t-test or with the Mann-Whitney test. Uni- and multi-variate logistic regression analyses were used to test for a possible relationship between intramural ATs and ARIs with appearance of J-waves on the surface ECG and VF. The differences were considered significant at p < 0.05.Data are expressed as medians and interquartile intervals. Statistical analysis was performed with the SPSS package (IBM SPSS Statistics 23). According to the Kolmogorov-Smirnov normality test, either parametric . The most common type of VF initiation  and RCA  occlusions. In a whole group , AT max was associated with both J-wave  and VF  incidence. In the animals that survived until the end of occlusion , univariate analysis also showed that AT max was associated with J-wave development in LAD , RCA  occlusions, and in the whole No-VF group .In the baseline state, ATs were relatively uniform throughout ventricular myocardium, and AT max was usually observed in the basal regions. During ischemic exposure, AT max was found in the ischemic or border areas according to location of occlusion LAD or RCA). The ischemic regions were a middle part of IVS and a base of the lateral RV wall in LAD and RCA groups, respectively. During occlusion of both arteries, AT max similarly increased in a biphasic manner with two maxima at approximately 5 and 20–30 min of ischemic episode. A. The isp = 0.003; and 213 (IQR 157–287) ms at 40th min of RCA occlusion vs. 253 (IQR 186–316) ms in baseline, p = 0.030].Durations of maximal ARIs (consistently observed in the nonischemic zones) demonstrated no significant changes in comparison with baseline in both LAD and RCA groups . By the p < 0.001]. At the apical level, ARIs did not differ between RV and LV . Multiple comparisons of ARIs at each time-point during ischemia vs. baseline showed different dynamics in the LAD and RCA groups  ms vs. 302 (259–316) ms, respectively; A groups . The forp = 0.001, respectively, p < 0.001, n = 14) and RCA  groups. In the combined group (LAD + RCA), ΔARI was also associated with J-wave occurrence  but not with VF . The similar dynamics of ΔARI was shown in the animals survived the entire 40 min period of occlusion , RCA , and combined LAD + RCA  groups.Irrespectively of the infarct-related artery, ∆ARI was significantly higher in the presence of J-waves in the body surface ECGs [97 (IQR 71–155) vs. 49 (IQR 29–97) ms, cclusion ,D. In thp < 0.001 and OR = 1.016 95% CI 1.007–1.025, p = 0.001, respectively, n = 15) of J-wave appearance on ECG during coronary occlusion of both localizations. A scatter plot in p < 0.001). These cases are indicated by blue circles in a domain of negative ARI shortening (that means ARI prolongation). Collectively, these findings suggest independent contribution to J-wave generation from depolarization and repolarization changes.In multivariate logistic regression analysis, it was shown that both AT max and ΔARI  were independent predictors  current among other causes . This condition is met under ischemia when the activation wave is slowly spreading toward a positive lead terminal across the ischemic area. Similarly, J-wave appeared under inhibition of sodium current . In the to current density  current in the LV as compared to the RV. Moreover, ARIs in the RV base were shorter in baseline and probably had less repolarization reserve. Anyway, the ΔARI parameter was an independent predictor of J-wave appearance both in uni- and multi-variate (together with activation delay) analysis, both in LAD- and RCA-occlusion groups separately as well as in combination.The repolarization-related predictor of J-wave development used in our present study was the difference between the “ischemic”  ARI and ARI in the normal myocardium. Using this parameter, we assumed that the greater was this duration difference, the greater was the potential difference between these regions, and therefore the greater was the electric field responsible for J-wave development. Interestingly, we observed much less ΔARI in RCA occlusion, whereas dynamics of ATs were quite similar in the RV and LV ischemic areas under RCA and LAD occlusion, respectively. Though the different repolarization responses to ischemia cannot be explained directly by the data obtained, this observation is consistent with the findings of The interest to J-waves as a distinct ECG phenomenon is well-understood taking into account its potential use as a predictor of fatal ventricular arrhythmias. However, it was pointed out that not every ever observed J-wave necessarily predicts ventricular fibrillation or sudden cardiac death . Our preThus, in the open chest model of myocardial infarction, repolarization abnormalities expressed as a difference in ARIs between the normal and ischemic myocardium contributed to J-waves formation together with activation delay, but did not predict VF occurrence, which was associated only with activation slowing.in vivo recorded myocardial electrograms can be considered as reliably validated (Estimation of action potential duration as ARI obtained from the alidated . Howeveralidated  suggest Ischemic conditions impose additional limitations on interpretation of measured ARIs since morphology of action potentials is significantly altered under ischemia. However, ARI measurements and analysis are still feasible in such settings . MoreoveThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Ethical Committee of the Institute of Physiology of the Komi Science Centre, Ural Branch of Russian Academy of Sciences.AT, JA, OB, AO, MD, and PP contributed to the design. AT, JA, OB, AO, MV, and MD contributed to the experiments. AT, JA, AO, and MV contributed to the data analysis. AT and JA drafted the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Metagenomics studies provide valuable insight into the composition and function of microbial populations from diverse environments; however, the data processing pipelines that rely on mapping reads to gene catalogs or genome databases for cultured strains yield results that underrepresent the genes and functional potential of uncultured microbes. Recent improvements in sequence assembly methods have eased the reliance on genome databases, thereby allowing the recovery of genomes from uncultured microbes. However, configuring these tools, linking them with advanced binning and annotation tools, and maintaining provenance of the processing continues to be challenging for researchers.Here we present ATLAS, a software package for customizable data processing from raw sequence reads to functional and taxonomic annotations using state-of-the-art tools to assemble, annotate, quantify, and bin metagenome data. Abundance estimates at genome resolution are provided for each sample in a dataset. ATLAS is written in Python and the workflow implemented in Snakemake; it operates in a Linux environment, and is compatible with Python 3.5+ and Anaconda 3+ versions. The source code for ATLAS is freely available, distributed under a BSD-3 license.https://github.com/metagenome-atlas/atlas.ATLAS provides a user-friendly, modular and customizable Snakemake workflow for metagenome data processing; it is easily installable with conda and maintained as open-source on GitHub at  Metagenomics has transformed microbial ecology studies with the ability to generate genome sequence information from environmental samples, yielding valuable insight into the composition and functional potential of natural microbial populations from diverse environments , 2. DespThe most direct and frequently used way to analyze metagenome data is to map the sequence reads to reference genomes, when a suitable genome database from cultivated microbes is available (e.g. Humann2 ). HoweveA number of assembly-based metagenome pipelines have been developed, each providing a subset of the required tools needed to carry out a complete analysis process from raw data to annotated genomes –17. For Here we present an entirely new version of ATLAS , an assehttps://metagenome-atlas.rtfd.io).The ATLAS framework organizes sequence data processing tools into four distinct analysis modules:  quality clumpify is used remove PCR duplicates and compress the raw data files, followed by BBduk to remove known adapters, trim and filter reads based on their quality and length (respectively), and error-correct overlapping paired-end reads where applicable. BBSplit is used to remove contaminating reads using reference sequences: PhiX is provided as a default or can be replaced by user-specified fasta-format sequences. To optimize data use, reads that lose their mate during these steps are seamlessly integrated into the later steps of the pipeline.Quality control of raw sequence data, in the form of single- or paired-end FASTQ files, is performed using utilities in the BBTools suite . SpecifiTadpole) and paired-end read merging (bbmerge). If paired-end reads do not overlap, bbmerge can extend them using read-derived overlapping k-mers. ATLAS uses metaSPAdes [Prior to metagenome assembly, ATLAS uses additional BBTools utilities  to perfotaSPAdes  or MEGAHtaSPAdes , 26 for The prediction of metagenome-assembled genomes (MAGs) allows organism-specific analyses of metagenome datasets. In ATLAS, two binning methods are implemented Fig. : metabatBecause the same genome may be identified in multiple samples, dRep  is used For annotation, ATLAS supports the prediction of open reading frames (ORFs) using Prodigal . The traThe ATLAS output for each sample includes the quality-controlled reads, assembled contigs, bam files (reads mapped to contigs), and predicted genome bins, together with summary statistics in an HTML report. The final output includes results from all samples, including the raw and normalized counts for the set of non-redundant, high-quality MAGs, with a quality report and their inferred taxonomy. From the annotation stage, two fasta files are produced containing the nucleotide and amino acid sequences of the representative genes in the non-redundant gene catalog, together with a table containing the gene annotations summarized at the genome level.Bacteroides were more abundant than Firmicutes, in both cecum and feces .Figure ces Fig. C,D. A prces Fig. E. DetailATLAS is easy to install and provides documented and modular workflows for the analysis of metagenome data. The internal codes utilized by the workflow are highly configurable using either a configuration file or via the command line. ATLAS provides a robust bioinformatics framework for high-throughput sequence data, where raw FASTQ files can be fully processed into annotated tabular files for downstream analysis and visualization. ATLAS fills a major analysis gap, namely the integration of tools for quality control, assembly, binning and annotation, in a manner that supports robust and reproducible analyses. ATLAS provides these analysis tools in a command-line interface amenable to high-performance computing clusters.https://github.com/metagenome-atlas/atlas, with example data provided for testing. Software documentation is available at https://metagenome-atlas.rtfd.io, which describes the installation and use of ATLAS including a Docker container (https://hub.docker.com/r/metagenomeatlas/atlas).The source code for ATLAS is distributed under a BSD-3 license and is freely available at Availability Project name: ATLAS.https://github.com/metagenome-atlas/atlasProject home page: Archived version: 10.1101/737528Operating system(s): Linux.Programming language: Snakemake/Python.Other requirements: Miniconda.License: BSD-3.Any restrictions to use by non-academics: None.


GBA) gene are among the most common genetic risk factors for the development of Parkinson's disease (PD). Yet, penetrance is markedly reduced, and less is known about the burden of carrying a single mutation among those without diagnosed PD. Motor, cognitive, psychiatric, and olfactory functioning were assessed in 30 heterozygous GBA mutation carriers without PD (the majority of whom had mild GBA mutations) and 49 non-carriers without PD. Study focus was on domains affected in GBA mutation carriers with PD, as well as those previously shown to be abnormal in GBA mutation carriers without PD. GBA mutation carriers showed poorer performance on the Stroop interference measure of executive functioning when controlling for age. There were no group differences in verbal memory, Montreal Cognitive Assessment (MoCA), overall motor score, or presence of REM sleep behavior disorder or depression. Although total olfaction scores did not differ, GBA mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. As anticipated by the low penetrance of GBA mutations, these findings suggest that pre-manifest non-motor or motor features of PD may not present in most GBA mutation carriers. However, there is support that there may be a subtle difference in executive functioning among some non-manifesting heterozygous GBA mutation carriers, and, combined with olfaction, this may warrant additional scrutiny as a potential biomarker for pre-manifest and pre-clinical GBA related PD.Mutations and variants in the glucocerebrosidase ( GBA mutations are a common genetic risk factor for Parkinson disease (PD) and dementia with Lewy Bodies (DLB)  may have earlier age of onset and more prominent non-motor features than idiopathic PD  –3. Whileathic PD –6. This athic PD  and demeathic PD –10. GBA-ctioning , and visctioning . Further , displayed a PD phenotype that was similar to non-mutation, sporadic PD, during the first 3 years of clinical disease , which may be attributable to mutation type and ascertainment. Studies investigating cohorts of mild or mild and severe mutation carriers ascertained in clinical settings and thus often consisting of relatives of individuals with PD,  or mutation negative control was based on the results of genotyping, and some spouses of PD patients harbored GBA mutations. GBA mutation/variant status was determined as previously described  as well as E365K, T408M, and the G2019S LRRK2 mutation. The Tag-It™ Mutation Detection Kit  was used to perform genotyping according to the manufacturer's instructions. Using this system, the regions around the target genes were amplified by multiplex polymerase chain reaction (PCR). The regions were subjected to allele-specific primer extension, hybridized to specific Luminex® beads via Universal Tags, and sorted on a Luminex® 100 IS platform . Genotyping was then completed using the Tag-It™Data Analysis Software (Luminex Molecular Diagnostics).Inclusion as either a non-manifesting escribed , 25. In Participants provided written informed consent, and this study protocol was approved by the Mount Sinai Institutional Review Board.Systematic neurological history and examination, including Unified Parkinson Disease Rating Scale-III (UPDRS-III), was completed by a neurologist. Non-motor symptoms were assessed using neuropsychological measures, administered by trained coordinators under the guidance of a clinical neuropsychologist. The following cognitive measures were used: Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test—Revised (HVLT-R), Stroop Test, Color Trails Test, Symbol Digit Modality Test, Digit Span, Letter Number Sequencing, Judgment of Line Orientation, FAS, and Animal Fluency.Additional non-motor features were assessed using the Beck Depression Inventory—II (BDI-II), State-Trait Anxiety Inventory (STAI), REM Sleep Behavior Disorder Questionnaire (RBDQ), and University of Pennsylvania Smell Identification Test (UPSIT).GBA-NMC and controls in motor functioning , executive function (Stroop), and MoCA. Primary motor comparisons were associated with continuous UPDRS-III scores. Depression (BDI-II) and RBD (RBDQ) were assessed using recommended cut scores of 14 and 5, respectively. As there are two major methods to assess olfaction, olfactory performance on the UPSIT was compared both continuously and dichotomously, using a cut-off score of 15 percentile adjusted for age and gender to define hyposmia , two with a severe mutation (2 84GG), and four with other PD associated risk variants , and 49 did not (controls). Among 30 GBA-NMC, 20 were recruited through a blood family member with PD, and 10 were spouses or friends. Seventeen GBA-NMC and 7 controls had a family history of PD in a first degree relative. Among the control group (non-GBA), all of whom were spouse (36) or friend  were not older than controls . There were no group differences in sex  or years of education . UPDRS-III, MoCA, HVLT-R Z-score, and Stroop interference T-score, and UPSIT scores did not differ between groups.GBA mutation (p < 0.05), whereas UPDRS-III, HVLT-R, MoCA, UPSIT, presence, or significant symptoms of RBD or depression were not.GBA-NMC and controls in the remaining cognitive measures listed above, or in anxiety, when correcting for multiple comparisons.In the exploratory analyses, no difference was found between GBA-NMC were hyposmic, and 24% of controls were hyposmic. Among GBA-NMC, those with hyposmia had lower scores on the MoCA when controlling for age, (p = 0.018), with both hyposmia (p = 0.046) and age (p = 0.019) as significant predictors of MoCA score. Hyposmia was not significantly related to other primary outcome variables.Forty percent of GBA mutation status and symptoms related to PD. GBA mutation carriers showed poorer performance on the inhibition component of the Stroop task. While there were no overall group differences in global cognitive functioning, assessed by the MoCA, GBA mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. Additionally, GBA carriers were more likely to exhibit subtle motor signs.Findings from this study detail key associations between GBA mutation carriers with and without parkinsonism , albeit with a focus on mild mutation carriers. Most studies have reported worse performance on the MoCA among individuals with GBA-PD relative to idiopathic PD  have previously demonstrated greater cortical activation during a task of response inhibition . This differs from results of a recent large, multicenter, study reporting worse performance on the MoCA among both GBA-NMC and LRRK2-NMC relative to control participants  or risk variants . Penetrance of  reduced , and as  reduced , 23 may GBA-NMC and control participants with and without family members with PD. Some of our sample was ascertained through affected family members, and others were spouses of individuals with idiopathic PD. Similar to other studies in which non-manifesting carriers and controls were recruited through tertiary care clinics, our participants with first degree relatives with PD, likely share additional risk factors that were not directly accounted for in this study, and a larger proportion of individuals with such a family history were in the GBA-NMC cohort. To determine the degree to which included mutation negative, but positive family history controls influenced the analysis, sensitivity analyses were performed, in which individuals in the control group with a family history of PD were excluded. These yielded a similar pattern yet did not reach statistical significance. Mutation carriers continued to show poorer performance on the inhibition component of the Stroop task when controlling for age, although this finding no longer reached statistical significance. In excluding these individuals, it is possible this analysis was limited by the reduced sample size. However, additional unmeasured genetic and environmental factors seen in family members of affected individuals interact with GBA status, and contribute to the differences measured.Through our sample, we identified both GBA associated PD risk (GBA status.Additionally, as limited genetic testing was available for this study, we are unable to conclusively determine if presence of additional genetic factors that may be associated with PD impact our findings. As additional genetic factors may modify  PD risk , along wGBA-NMC and mutation negative controls on non-motor features. While statistically significant differences emerged, it is notable that across domains assessed in this study, these differences were reflective of mild vulnerabilities. Motor functioning was within normal limits, and cognitive findings were limited to one domain, and reflective of mild, relative weakness, rather than significant burden. While such differences may be suggestive of an emerging pathological process, the overall disease burden was low in this sample. Our study was limited in that we were not able to disentangle the effect of mutation severity, as the sample of severe and risk variant carriers was low. Further, additional longitudinal investigations are needed to determine if these mild differences represent prodromal disease.This study reports subtle differences between The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Mount Sinai Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.RS-P and EM: study concept and design. EM, RS-P, and MZ: drafting of the manuscript. EM, RS-P, CW, and RO: Statistical analysis. RS-P and MZ: study supervision. RS-P: obtained funding. All authors: acquisition, analysis, or interpretation of data, critical revision of the manuscript for important intellectual content, administrative, technical, or material support.SB and RS-P have received consulting fees from Denali Therapeutics Inc. 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.


Objectives: Food cravings may cause weight gain in patients with schizophrenia. This study investigated psychological characteristics associated with food cravings in patients with first-episode psychosis.Methods: This study analyzed data from a clinical cohort of first-episode psychosis patients taking antipsychotics for 3 months or less. The strength of food cravings was measured using the General Food Cravings Questionnaire-Trait (G-FCQ-T). Psychological characteristics and psychiatric symptoms were investigated with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Social and Occupational Functioning Assessment Scale, Rosenberg Self-Esteem Scale (RSES), and Perceived Stress Scale (PSS). Clinical characteristics were compared according to significant weight gain (≥10% increase in body weight compared to baseline) over 3 months. Associations between the G-FCQ-T and other psychiatric scales were investigated. We conducted sex-stratified analyses.Results: In total, 182 patients  with first-episode psychosis were enrolled in this study. In females, the G-FCQ-T total score at baseline was associated with baseline body weight and significant weight gain over 3 months. The PSS scales were significantly associated the G-FCQ-T total and all subscale scores in female participants. Scores on the RSES and CDSS were significantly associated with the G-FCQ-T total score and with the preoccupation and loss of control subscale scores. The PANSS negative and general subscales were significantly associated with the positive outcome expectancy and loss of control subscales of the G-FCQ-T, respectively. In males, the only significant association was between the loss of control subscale and RSES scores. Linear regression analysis showed significant associations of PSS scores with the total and all subscale scores of the G-FCQ-T despite the loss of significance for other variables.Conclusion: These results indicate that the food cravings in patients with first-episode psychosis, which were associated with weight gain, were influenced by perceived stress in females. To reduce food cravings in female patients with schizophrenia, interventions aimed at perceived stress should be considered. The relative risk of obesity in patients with schizophrenia is 1.5–2 times higher than that in the general population . A meta-Maintenance treatment with antipsychotics is essential for patients with schizophrenia, although those who are also obese are twice as likely to discontinue using their medication . SeveralAntipsychotic treatment has a significant effect on weight gain –21. HoweIn the general population, certain eating habits, food cravings, and psychological factors are associated with body weight and weight gain , 27. HigMost previous studies on weight gain in patients with schizophrenia have focused on biological factors, including the type of antipsychotics used, rather than on psychosocial and behavioral factors. In addition, weight gain in patients with schizophrenia occurs early in the disease course . HoweverThis study hypothesized that (i) food cravings are associated with weight gain in patients with first-episode psychosis, and (ii) various psychological factors can contribute to food cravings. To minimize confounding factors, only patients with first-episode psychosis, and those using antipsychotics with a low to moderate propensity to cause gain weight, were included in this study. In addition, we conducted sex-stratified analyses to account for possible sex differences in eating patterns.This study analyzed the data of an early-psychosis cohort enrolled in the Gwangju Early Treatment and Intervention Team (GETIT) study . The GETBaseline sociodemographic and clinical data included age, sex, diagnosis, type of antipsychotics taken, dosage of chlorpromazine equivalent dosage , duratioThe strength of food cravings was measured using the General Food Cravings Questionnaire-Trait (G-FCQ-T), which is a 21-item self-report measure of the general “desire for food” or “desire to eat.”  and formOther psychological characteristics and psychiatric symptoms were investigated using the Positive and Negative Syndrome Scale (PANSS) , Calgaryt-tests for normally distributed variables (tested by the Kolmogorov-Smirnov test), and Mann-Whitney U tests for non-normally distributed variables, as appropriate. All clinical scales submitted to statistical analyses were measured at baseline. A two-way analysis of variance (ANOVA) with interactions was conducted to compare participants' clinical scale scores according to sex and significant weight gain. Then, statistical analyses were separately conducted in males and females. Scores on the G-FCQ-T and psychiatric scales were compared between the two groups divided by significant weight gain using an analysis of covariance after controlling for baseline body weight. Associations between G-FCQ-T scores and psychiatric scales were investigated using Pearson's correlation test for normally distributed variables and Spearman's correlation test for non-normally distributed variables. Age and variables that were significantly associated with G-FCQ-T scores at the p <0.05 level were entered into linear regression analysis to control for confounding effects. Non-normally distributed variables were entered into the regression model after log transformation. The sample size calculated using GPower for a correlation test with a power of 0.80 and an alpha of 0.05 for a medium effect size (0.3) was 84 for each sex. All statistical tests were two-tailed and p < 0.05 was taken to indicate statistical significance. The statistical analysis was performed using SPSS software .Comparisons of clinical characteristics according to “clinically significant weight gain,” defined as a ≥10% increase in body weight after 3 months compared to baseline, were conducted using the chi-square test for categorical variables, independent t = −1.891, p = 0.060). Aripiprazole, amisulpride, and paliperidone were prescribed in 36 (19.8%), 57 (31.3%), and 89 patients (48.9%), respectively. Scores on the G-FCQ-T were not significantly associated with type and chlorpromazine equivalent dosage of antipsychotic medication .A total of 182 patients  with first-episode psychosis were enrolled in this study. The media (interquartile range) age at baseline was 25.5 (21.0–32.0) years. The median (interquartile range) duration of treatment and DUP were 1 (0.6–1.5) and 3 (1–12) months, respectively. There were no significant sex differences in these variables. The scores on the G-FCQ-T did not differ significantly between sexes. The scores on the emotional craving subscale of the G-FCQ-T tended to be higher in females than in males, but the difference was not statistically significant . A total of 150 patients (82.4%) completed the 3-month follow-up evaluation of weight gain. Clinically significant weigh gain was found in 44 patients (29.3%). Pearson correlation coefficients between the G-FCQ-T scores and baseline body weight were significant only for the loss of control subscale and total scores in female patients . The RSES score was lower in the weight gain group than in the non-weight gain group for females, and it was higher in the weight grain group than the non-weight gain group for males; the results of separate analyses in each sex were not statistically significant . Spearman correlation analyses showed no significant associations among G-FCQ-T scores, DUP, and duration of treatment . Spearman correlation analysis showed that the G-FCQ-T total score was significantly associated with age in the female population (Weight gain in patients with schizophrenia begins in the early stage of the disease and rapidly worsens; thus, early intervention is important. In this study, we found that significant weight gain was prevalent in patients who recently started taking antipsychotic medications. Additionally, body weight and weight gain during treatment were significantly associated with food cravings in female patients with first-episode psychosis, but not in males. Associations between food cravings and psychological variables, such as perceived stress, were also prominent in females. There was no significant difference in the degree of food cravings or weight gain according to the type and dosage of antipsychotic drug being taken. To reduce food cravings and uncontrolled eating in patients with schizophrenia, and particularly in females, interventions aimed at perceived stress should be considered. To our knowledge, this is the first study to identify sex-specific associations among food craving, weight gain, and psychological factors in patients with first-episode psychosis.This study results were consistent with previous studies on the general population showing that food cravings were associated with body weight  and weigSex differences in eating patterns have been noted in the general population, with women usually showing higher levels of dietary restraint and disinhibition than men . In addiThe stress response is generated by activity in two interacting pathways: the sympathetic adrenal medullary system, in which the release of catecholamines is typical during periods of acute stress , and theMoreover, depressive symptoms, usually accompanied by chronic stress, are associated with a preference for snack/fast food and sweet food , 69, andIn this study, negative symptoms were inversely associated with positive outcome expectancy relative to food cravings. This finding indicates that negative symptoms such as avolition and anhedonia might inversely affect food cravings in a manner opposite the positive associations found between food cravings and emotional factors such as perceived stress and depression.Low self-esteem and negative affect have frequently been hypothesized as key features of binge eating, including in the cognitive-behavioral model of bulimia nervosa , escape This study had a few limitations. First, in this study, patients taking antipsychotics with a low to moderate propensity to cause weight gain  were selOur study suggests that psychological mechanisms mediating weight gain in patients with schizophrenia may differ according to sex. Food cravings associated with weight gain in female patients with first-episode psychosis were influenced by emotional factors such as perceived stress. Interventions targeting perceived stress may be necessary to promote control of eating behaviors. Psychological factors and eating habits merit more attention, particularly in female patients with schizophrenia, to prevent weight gain. We believe that our findings can contribute to the development of effective interventions to prevent weight gain in patients with schizophrenia.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Chonnam National University Hospital Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.Y-HK, MK, MJ, and S-WK have contributed to the conception and design of the study. S-WK and Y-CC organized the database. S-WK performed the statistical analysis. Y-HK wrote the first draft of the manuscript. SR, H-JN, J-YL, J-MK, and MS critically revised the draft. All authors read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.