Effective Rapid Diagnosis of Bacterial and Fungal Bloodstream Infections by T2 Magnetic Resonance Technology in the Pediatric Population.

Children are prone to bloodstream infections (BSIs), the rapid and accurate diagnosis of which is an unmet clinical need. The T2MR technology is a direct molecular assay for identification of BSI pathogens, which can help to overcome the limits of blood culture (BC) such as diagnostic accuracy, blood volumes required, and turnaround time. We analyzed results obtained with the T2Bacteria (648) and T2Candida (106) panels in pediatric patients of the Bambino Gesù Children's Hospital between May 2018 and September 2020 in order to evaluate the performance of the T2Dx instrument with respect to BC. T2Bacteria and T2Candida panels showed 84.2% and 100% sensitivity with 85.9% and 94.1% specificity, respectively. The sensitivity and specificity of the T2Bacteria panel increased to 94.9% and 98.7%, respectively, when BC was negative but other laboratory data supported the molecular result. T2Bacteria sensitivity was 100% with blood volumes <2 mL in neonates and infants. T2Bacteria and T2Candida provided definitive microorganism identification in a mean time of 4.4 and 3.7 h, respectively, versus 65.7 and 125.5 h for BCs (P < 0.001). T2 panels rapidly and accurately enable a diagnosis of a pediatric BSI, even in children under 1 year of age and for very small blood volumes. These findings support their clinical use in life-threatening pediatric infections, where the time to diagnosis is of utmost importance, in order to improve survival and minimize the long-term sequalae of sepsis. The T2 technology could be further developed to include more bacteria and fungi species that are involved in the etiology of sepsis.

SARS-CoV-2 RNA in plasma samples of COVID-19 affected individuals: a cross-sectional proof-of-concept study.

BACKGROUND: Recent studies showed that plasma SARS-CoV-2 RNA seems to be associated with worse COVID-19 outcome. However, whether specific population can be at higher risk of viremia are to date unexplored. METHODS: This cross-sectional proof-of-concept study included 41 SARS-CoV-2-positive adult individuals (six affected by haematological malignancies) hospitalized at two major hospital in Milan, for those demographic, clinical and laboratory data were available. SARS-CoV-2 load was quantified by ddPCR in paired plasma and respiratory samples. To assess significant differences between patients with and patients without viremia, Fisher exact test and Wilcoxon test were used for categorical and continuous variables, respectively. RESULTS: Plasma SARS-CoV-2 RNA was found in 8 patients (19.5%), with a median (IQR) value of 694 (209-1023) copies/mL. Viremic patients were characterized by an higher mortality rate (50.0% vs 9.1%; p = 0.018) respect to patients without viremia. Viremic patients were more frequently affected by haematological malignancies (62.5% vs. 3.0%; p < 0.001), and had higher viral load in respiratory samples (9,404,000 [586,060-10,000,000] vs 1560 [312-25,160] copies/mL; p = 0.002). CONCLUSIONS: Even if based on a small sample population, this proof-of-concept study poses the basis for an early identification of patients at higher risk of SARS-CoV-2 viremia, and therefore likely to develop severe COVID-19, and supports the need of a quantitative viral load determination in blood and respiratory samples of haematologic patients with COVID-19 in order to predict prognosis and consequently to help their further management.

The child and adolescent psychiatry: study of training in Europe (CAP-STATE).

There is great cultural diversity across Europe. This is reflected in the organisation of child and adolescent mental health (CAMH) services and the training of the respective professionals in different countries in Europe. Patients and their parents will want a high quality, knowledgeable, and skillful service from child and adolescent psychiatrists (CAPs) wherever they see them in Europe. A European comparison of training programs allows all stakeholders in different European countries to assess the diversity and to initiate discussions as to the introduction of improvements within national training programs. Major issues to be addressed in comparing child and adolescent psychiatric training programs across Europe include: (1) formal organisation and content of training programs and the relationship to adult psychiatry and paediatrics; (2) flexibility of training, given different trainee interests and that many trainees will have young families; (3) quality of governance of training systems; (4) access to research; and (5) networking. The Child and Adolescent Psychiatry-Study of Training in Europe (CAP-State) is a survey of training for child and adolescent psychiatrists (CAPs) across European countries. It aims to revisit and extend the survey carried out in 2006 by Karabekiroglu and colleagues. The current article is embedded in a special issue of European Child + Adolescent Psychiatry attempting to for the first time address training in CAP at the European and global levels. Structured information was sought from each of 38 European and neighboring countries (subsequently loosely referred to as Europe) and obtained from 31. The information was provided by a senior trainee or recently qualified specialist and their information was checked and supplemented by information from a senior child and adolescent psychiatry trainer. Results showed that there is a very wide range of provision of training in child and adolescent psychiatry in different countries in Europe. There remains very substantial diversity in training across Europe and in the degree to which it is subject to national oversight and governance. Some possible reasons for this variation are discussed and some recommendations made.

Correction to: The child and adolescent psychiatry: study of training in Europe (CAP­STATE).

The original article has been corrected.

Inhibition of CCR7/CCL19 axis in lesional skin is a critical event for clinical remission induced by TNF blockade in patients with psoriasis.

Despite the evidence that tumor necrosis factor (TNF) inhibitors block TNF and the downstream inflammatory cascade, their primary mechanism of action in inhibiting the self-sustaining pathogenic cycle in psoriasis is not completely understood. This study has the aim to identify early critical events for the resolution of inflammation in skin lesions using anti-TNF therapy. We used a translational approach that correlates gene expression fold change in lesional skin with the Psoriasis Area and Severity Index score decrease induced by TNF blockade after 4 weeks of treatment. Data were validated by immunofluorescence microscopy on skin biopsy specimens. We found that the anti-TNF-modulated genes that mostly associated with the clinical amelioration were Ccr7, its ligand, Ccl19, and dendritic cell maturation genes. Decreased expression of T-cell activation genes and Vegf also associated with the clinical response. More important, the down-regulation of Ccr7 observed at 4 weeks significantly correlated with the clinical remission occurring at later time points. Immunofluorescence microscopy on skin biopsy specimens showed that reduction of CCR7(+) cells and chemokine ligand (CCL) 19 was paralleled by disaggregation of the dermal lymphoid-like tissue. These data show that an early critical event for the clinical remission of psoriasis in response to TNF inhibitors is the inhibition of the CCR7/CCL19 axis and support its role in psoriasis pathogenesis.

Drug attitude in adolescents: a key factor for a comprehensive assessment.

OBJECTIVE: Very few studies have evaluated the subjective experience (SE) in children and adolescents treated with antipsychotics. The present study aimed to evaluate the SE of antipsychotics in adolescents diagnosed with different psychiatric conditions and to identify explanatory variables of adolescents' SE and compliance with treatment. METHODS: The Drug Attitude Inventory (DAI) was used to evaluate SE in 67 adolescents in 2 different countries (Italy and United Kingdom). Compliance was measured using a Likert scale completed by both patients and parents. To evaluate other parameters correlated to the SE, the following scales were administered: Clinical Global Impression Scale, Children's Global Assessment Scale, Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, and EuroQoL (for quality of life). Multiple and logistic regression analyses were applied. RESULTS: No significant difference in drug attitude was found between psychotic and nonpsychotic patients. Our results showed a highly significant association between DAI and compliance (Spearman index, 0.33; P = 0.005); for all other variables, DAI associated significantly only with quality of life (r = 0.25; P = 0.03). The multivariable analysis confirmed the presence of a strong association between compliance and DAI (P = <0.001). In our sample, drug attitude was the only variable found to be correlated with the compliance, whereas extrapyramidal adverse effects showed an only marginally significant association. CONCLUSIONS: Our observations provide confirmation, also in adolescents, that drug attitude is strongly correlated with treatment compliance and underline the need in clinical assessments to always consider the patient's viewpoint.

Psychopathological symptoms in child and adolescent migraine and tension-type headache: a meta-analysis.

INTRODUCTION: After decades of research, the importance of psychological factors in child and adolescent headache is no longer in doubt. However, it is not clearly understood whether different types of headache are comorbid with specific kinds of psychopathology. To address this issue, we set out to establish whether young patients with migraine do or do not show significant levels of psychopathological symptoms compared with age-matched healthy controls and patients with tension-type headache (TTH). METHODS: Ten studies were selected on the basis of a widely used psychodiagnostic tool (the Child Behavior Checklist (CBCL)) and by applying rigorous criteria: The studies were compared in a meta-analysis in order to evaluate the presence of Internalizing (mainly anxiety and depression) and Externalizing (mainly behavioral problems) symptoms in different types of headache (and versus healthy controls). FINDINGS: Patients with migraine showed more psychopathological symptoms than healthy controls. TTH patients also had more psychopathology than controls, although the difference was more marked in the area of Internalizing disorders. Finally, no differences emerged between migraine and TTH. DISCUSSION AND CONCLUSION: Psychopathological symptoms affect children with migraine, but also children with TTH. Biological, pathophysiological and clinical links need to be established. Effective treatment of affected children and adolescents is imperative in order to prevent chronic evolution. In this context, the CBCL may be a good screening instrument with a view to developing a tailored clinical approach.

Artificial intelligence for differentiating COVID-19 from other viral pneumonias on CT: comparative analysis of different models based on quantitative and radiomic approaches.

BACKGROUND: To develop a pipeline for automatic extraction of quantitative metrics and radiomic features from lung computed tomography (CT) and develop artificial intelligence (AI) models supporting differential diagnosis between coronavirus disease 2019 (COVID-19) and other viral pneumonia (non-COVID-19). METHODS: Chest CT of 1,031 patients (811 for model building; 220 as independent validation set (IVS) with positive swab for severe acute respiratory syndrome coronavirus-2 (647 COVID-19) or other respiratory viruses (384 non-COVID-19) were segmented automatically. A Gaussian model, based on the HU histogram distribution describing well-aerated and ill portions, was optimised to calculate quantitative metrics (QM, n = 20) in both lungs (2L) and four geometrical subdivisions (GS) (upper front, lower front, upper dorsal, lower dorsal; n = 80). Radiomic features (RF) of first (RF1, n = 18) and second (RF2, n = 120) order were extracted from 2L using PyRadiomics tool. Extracted metrics were used to develop four multilayer-perceptron classifiers, built with different combinations of QM and RF: Model1 (RF1-2L); Model2 (QM-2L, QM-GS); Model3 (RF1-2L, RF2-2L); Model4 (RF1-2L, QM-2L, GS-2L, RF2-2L). RESULTS: The classifiers showed accuracy from 0.71 to 0.80 and area under the receiving operating characteristic curve (AUC) from 0.77 to 0.87 in differentiating COVID-19 versus non-COVID-19 pneumonia. Best results were associated with Model3 (AUC 0.867 ± 0.008) and Model4 (AUC 0.870 ± 0.011. For the IVS, the AUC values were 0.834 ± 0.008 for Model3 and 0.828 ± 0.011 for Model4. CONCLUSIONS: Four AI-based models for classifying patients as COVID-19 or non-COVID-19 viral pneumonia showed good diagnostic performances that could support clinical decisions.

Diagnostic Performance in Differentiating COVID-19 from Other Viral Pneumonias on CT Imaging: Multi-Reader Analysis Compared with an Artificial Intelligence-Based Model.

Growing evidence suggests that artificial intelligence tools could help radiologists in differentiating COVID-19 pneumonia from other types of viral (non-COVID-19) pneumonia. To test this hypothesis, an R-AI classifier capable of discriminating between COVID-19 and non-COVID-19 pneumonia was developed using CT chest scans of 1031 patients with positive swab for SARS-CoV-2 (n = 647) and other respiratory viruses (n = 384). The model was trained with 811 CT scans, while 220 CT scans (n = 151 COVID-19; n = 69 non-COVID-19) were used for independent validation. Four readers were enrolled to blindly evaluate the validation dataset using the CO-RADS score. A pandemic-like high suspicion scenario (CO-RADS 3 considered as COVID-19) and a low suspicion scenario (CO-RADS 3 considered as non-COVID-19) were simulated. Inter-reader agreement and performance metrics were calculated for human readers and R-AI classifier. The readers showed good agreement in assigning CO-RADS score (Gwet's AC2 = 0.71, p < 0.001). Considering human performance, accuracy = 78% and accuracy = 74% were obtained in the high and low suspicion scenarios, respectively, while the AI classifier achieved accuracy = 79% in distinguishing COVID-19 from non-COVID-19 pneumonia on the independent validation dataset. The R-AI classifier performance was equivalent or superior to human readers in all comparisons. Therefore, a R-AI classifier may support human readers in the difficult task of distinguishing COVID-19 from other types of viral pneumonia on CT imaging.

Antibody Response to COVID-19 Booster Vaccination in Healthcare Workers.

Objective: To evaluate the mean increase of anti-S IgG antibody titer between the basal, pre-booster level to the titer assessed 14 days after the booster dose of BNT162b2. Patients and Methods: The RENAISSANCE study is an observational, longitudinal, prospective, population-based study, conducted on healthcare workers of Niguarda Hospital in Milan, Italy who received a BNT162b2 booster dose at least 180 days after their second dose or after positivity for SARS-CoV-2 and accepted to take part in the study. The RENAISSANCE study was conducted from January 1, 2021 through December 28, 2021. Findings: 1,738 subjects were enrolled among healthcare workers registered for the booster administration at our hospital. Overall, 0.4% of subjects were seronegative at the pre-booster evaluation, and 1 subject had a titer equal to 50 AU/ml: none of the evaluated subjects was seronegative after the booster dose. Thus, the efficacy of the booster in our population was universal. Mean increase of pre- to post-booster titer was more significant in subjects who never had SARS-CoV-2 (44 times CI 95% 42-46) compared to those who had it, before (33 times, CI 95% 13-70) or after the first vaccination cycle (12 times, CI 95% 11-14). Differently from sex, age and pre-booster titers affected the post-booster antibody response. Nevertheless, the post-booster titer was very similar in all subgroups, and independent of a prior exposure to SARS-CoV-2, pre-booster titer, sex or age. Conclusion: Our study shows a potent universal antibody response of the booster dose of BNT162b2, regardless of pre-booster vaccine seronegativity.

Prognostic Accuracy of DSM-5 Attenuated Psychosis Syndrome in Adolescents: Prospective Real-World 5-Year Cohort Study.

There is limited research in adolescents at risk for psychosis. The new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition attenuated psychosis syndrome (DSM-5 APS) criteria have not been validated in this group. We conducted a RECORD-compliant, real-world, prospective, 5-year cohort study addressing clinical profile, transition to psychosis, and prognostic accuracy of DSM-5 APS in help-seeking inpatient/outpatient adolescents accessing Children and Adolescent Neuropsychiatric services at IRCCS Mondino Foundation (Pavia, Lombardy, Italy) between 2012 and 2019. About 243 adolescents (31 early-onset psychosis [EOP]; 110 meeting DSM-5 APS criteria, DSM-5 APS; 102 not meeting psychotic or DSM-5 APS criteria, non-APS) were included. At baseline, DSM-5 APS adolescents (aged 15.4 ± 1.6) had on average 2.3 comorbid disorders (higher than EOP/non-APS, P < .001). DSM-5 APS adolescents had an intermediate psychopathological profile between non-APS/EOP (P < .001) and worsen Clinical Global Impression-Severity than non-APS (P < .001). DSM-5 APS functioning was intermediate between non-APS and EOP. 39.1% of DSM-5 APS were treated with psychotropic drugs (average = 64 days); 53.6% received psychotherapy. Follow-up of DSM-5 APS and non-APS groups lasted 33 and 26 months, respectively (median). The cumulative risk of transition at 1-5 years was 13%, 17%, 24.2%, 26.8%, and 26.8% in the DSM-5 APS group, 0%, 0%, 3.2%, 3.2%, and 3.2% in the non-APS group. The 5-year prognostic accuracy of the DSM-5 APS in adolescent was adequate (area under the curve = 0.77; Harrell's C = 0.736, 95%CI 0.697-0.775), with high sensitivity (91.3%) and suboptimal specificity (63.2%). The DSM-5 APS diagnosis can be used to detect help-seeking adolescents at risk of psychosis and predict their long-term outcomes. Future research should consolidate these findings.

Universal and Selective Interventions to Prevent Poor Mental Health Outcomes in Young People: Systematic Review and Meta-analysis.

BACKGROUND: Much is not known about the efficacy of interventions to prevent poor mental health outcomes in young people by targeting either the general population (universal prevention) or asymptomatic individuals with high risk of developing a mental disorder (selective prevention). METHODS: We conducted a PRISMA/MOOSE-compliant systematic review and meta-analysis of Web of Science to identify studies comparing post-test efficacy (effect size [ES]; Hedges' g) of universal or selective interventions for poor mental health outcomes versus control groups, in samples with mean age <35 years (PROSPERO: CRD42018102143). Measurements included random-effects models, I2 statistics, publication bias, meta-regression, sensitivity analyses, quality assessments, number needed to treat, and population impact number. RESULTS: 295 articles (447,206 individuals; mean age = 15.4) appraising 17 poor mental health outcomes were included. Compared to control conditions, universal and selective interventions improved (in descending magnitude order) interpersonal violence, general psychological distress, alcohol use, anxiety features, affective symptoms, other emotional and behavioral problems, consequences of alcohol use, posttraumatic stress disorder features, conduct problems, tobacco use, externalizing behaviors, attention-deficit/hyperactivity disorder features, and cannabis use, but not eating-related problems, impaired functioning, internalizing behavior, or sleep-related problems. Psychoeducation had the highest effect size for ADHD features, affective symptoms, and interpersonal violence. Psychotherapy had the highest effect size for anxiety features. CONCLUSION: Universal and selective preventive interventions for young individuals are feasible and can improve poor mental health outcomes.

A human stem cell-based model for identifying adverse effects of organic and inorganic chemicals on the developing nervous system.

The aim of our study was to investigate whether a human neural stem cell line derived from umbilical cord blood (HUCB-NSC) can serve as a reliable test model for developmental neurotoxicity (DNT). We assessed the sensitivity of HUCB-NSCs at different developmental stages to a panel of neurotoxic (sodium tellurite, methylmercury chloride, cadmium chloride, chlorpyrifos, and L-glutamate) and non-neurotoxic (acetaminophen, theophylline, and D-glutamate) compounds. In addition, we investigated the effect of some compounds on key neurodevelopmental processes like cell proliferation, apoptotic cell death, and neuronal and glial differentiation. Less differentiated HUCB-NSCs were generally more sensitive to neurotoxicants, with the notable exception of L-glutamate, which showed a higher toxicity to later stages. The relative potencies of the compounds were: cadmium chloride > methylmercury chloride >> chlorpyrifos >> L-glutamate. Fifty nanomolar methylmercury chloride (MeHgCl) inhibited proliferation and induced apoptosis in early-stage cells. At the differentiated stage, 1 muM MeHgCl induced selective loss of S100 beta-expressing astrocytic cells. One millimolar L-glutamate did not influence the early stages of HUCB-NSC development, but it affected late stages of neuronal differentiation. A valuable system for in vitro DNT assessment should be able to discriminate between neurotoxic and non-neurotoxic compounds and show different susceptibilities to chemicals according to developmental stage and cell lineage. Although not exhaustive, this work shows that the HUCB-NSC model fulfils these criteria and may serve as a human in vitro model for DNT priority setting.

Advanced Glycation End Products (AGE) and Soluble Forms of AGE Receptor: Emerging Role as Mortality Risk Factors in CKD.

Advanced glycation end-products (AGE) can promote chronic kidney disease (CKD) progression and CKD-related morbidities. The soluble receptor for AGE (sRAGE) is a potential biomarker of inflammation and oxidative stress. Here, we explored the role of AGE, glycated albumin, sRAGE and its different forms, cRAGE and esRAGE, as prognostic factors for mortality in 111 advanced CKD patients. The median follow-up time was 39 months. AGE were quantified by fluorescence, sRAGE and its forms by ELISA. Malnutrition was screened by the Malnutrition Inflammation Score (MIS). The Cox proportional hazards regression model was used to assess the association of variables with all-cause mortality. Mean levels of sRAGE, esRAGE and cRAGE were 2318 ± 1224, 649 ± 454 and 1669 ± 901 pg/mL. The mean value of cRAGE/esRAGE was 2.82 ± 0.96. AGE were 3026 ± 766 AU and MIS 6.0 ± 4.7. eGFR correlated negatively with AGE, sRAGE, esRAGE and cRAGE, but not with cRAGE/esRAGE. Twenty-eight patients died. No difference was observed between diabetic and non-diabetic patients. Starting dialysis was not associated with enhanced risk of death. AGE, esRAGE and cRAGE/esRAGE were independently associated with all-cause mortality. AGE, esRAGE and cRAGE/esRAGE may help to stratify overall mortality risk. Implementing the clinical evaluation of CKD patients by quantifying these biomarkers can help to improve patient outcomes.

Universal and selective interventions to promote good mental health in young people: Systematic review and meta-analysis.

Promotion of good mental health in young people is important. Our aim was to evaluate the consistency and magnitude of the efficacy of universal/selective interventions to promote good mental health. A systematic PRISMA/RIGHT-compliant meta-analysis (PROSPERO: CRD42018088708) search of Web of Science until 04/31/2019 identified original studies comparing the efficacy of universal/selective interventions for good mental health vs a control group, in samples with a mean age <35 years. Meta-analytical random-effects model, heterogeneity statistics, assessment of publication bias, study quality and sensitivity analyses investigated the efficacy (Hedges' g=effect size, ES) of universal/selective interventions to promote 14 good mental health outcomes defined a-priori. 276 studies were included (total participants: 159,508, 79,142 interventions and 80,366 controls), mean age=15.0 (SD=7.4); female=56.0%. There was a significant overall improvement in 10/13 good mental health outcome categories that could be meta-analysed: compared to controls, interventions significantly improved (in descending order of magnitude) mental health literacy (ES=0.685, p<0.001), emotions (ES=0.541, p<0.001), self-perceptions and values (ES=0.49, p<0.001), quality of life (ES=0.457, p=0.001), cognitive skills (ES=0.428, p<0.001), social skills (ES=0.371, p<0.001), physical health (ES=0.285, p<0.001), sexual health (ES=0.257, p=0.017), academic/occupational performance (ES=0.211, p<0.001) and attitude towards mental disorders (ES=0.177, p=0.006). Psychoeducation was the most effective intervention for promoting mental health literacy (ES=0.774, p<0.001) and cognitive skills (ES=1.153, p=0.03). Physical therapy, exercise and relaxation were more effective than psychoeducation and psychotherapy for promoting physical health (ES=0.498, p<0.001). In conclusion, several universal/selective interventions can be effective to promote good mental health in young people. Future research should consolidate and extend these findings.

Predictors of Outcomes in Adolescents With Clinical High Risk for Psychosis, Other Psychiatric Symptoms, and Psychosis: A Longitudinal Protocol Study.

In children and adolescents, schizophrenia is one of the ten main causes of disability-adjusted life years. The identification of people at Clinical High Risk of developing Psychosis (CHR-P) is one of the most promising strategies to improve outcomes. However, in children and adolescents research on the CHR-P state is still in its infancy and the clinical validity of at-risk criteria appears understudied in this population. Furthermore, only few studies have evaluated the psychopathological, neuropsychological, neuroimaging characteristics and, especially, long-term outcomes of adolescents at high risk. We present here the protocol of an innovative longitudinal cohort study of adolescents aged 12-17. The sample will consist of patients admitted to a third level neuropsychiatric unit, belonging to one of the following three subgroups: 1) adolescents with established Diagnostic and Statistical Manual of Mental Disorder-Fifth Edition psychosis, 2) adolescents with CHR-P, and 3) adolescents with psychiatric symptoms other than established psychosis or CHR-P. The primary aim of our study is to evaluate the 2-year prognosis across the three groups. We will measure transition to psychosis (or the stability of the diagnosis of psychosis in the psychotic group), the risk of development of other psychiatric disorders, as well as socio-occupational functioning at outcome. The secondary aim will be to explore the effect of specific predictors (clinical, neuropsychological and neuroimaging factors) on the prognosis. At baseline, 1-year and 2-year follow-up participants will be assessed using standardized semi-structured interviews and instruments. Psychopathological and functioning variables, as well as neuropsychological domains will be compared across the three subgroups. Moreover, at baseline and 2-year follow-up all recruited patients will undergo a 3-Tesla magnetic resonance imaging examination and diffusion tensor imaging parameters will be analyzed. We believe that this study will advance our ability to predict outcomes in underage CHR-P samples. In particular, our data will enable a better understanding of the clinical significance of CHR-P in adolescents, and shed new light on prognostic factors that can be used to refine the prediction of clinical outcomes and the implementation of preventive interventions.

Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib.

The use of proteasome inhibitors have been a major advance in the treatment of multiple myeloma (MM), but their mechanisms of action remain largely unclear. A better understanding of the cellular events downstream of proteasome inhibition is essential to improve the response and identify new combination therapies for MM and other malignancies. This study analysed the relationships between redox homeostasis and bortezomib treatment in MM cells. Our data showed that decreasing intracellular glutathione through buthionine sulfoximine treatment strongly enhances bortezomib toxicity, whilst antioxidants protect MM cells from bortezomib-mediated cell death. Bortezomib treatment decreases intracellular glutathione both in MM cell lines and in malignant plasma cells obtained from MM patients. Glutamate-cysteine ligase (GCLM) and haem-oxygenase-1 (HMOX1), two genes involved in the Nrf-2-mediated antioxidant response, as well as two eIF2alpha-downstream transcription factors, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), are upregulated, indicating that redox-related adaptive responses are initiated in bortezomib-treated MM cells. These findings demonstrate tight links between sensitivity to proteasome inhibition and redox homeostasis in MM cells and have potential implications for treatment.