The "3R Team" in action! Implementation of a program of learning from excellence in a neonatal and pediatric intensive care unit in France.

BACKGROUND: The pursuit of improving quality of care and of patient safety is a crucial objective in intensive care units (ICUs). Classically, safety is characterized by analyzing adverse events. Neonatal and pediatric ICUs (NICUs/PICU) are highly technological units, with evidence of risk for elevated levels of emotional exhaustion and thus a significant level of staff turnover. We hypothesized that appreciative inquiry (AI), currently used in many organizations, could be introduced in our ICU. In the PICU and NICU, this new concept is termed "learning from excellence" (LFE). OBJECTIVE: To assess the impact of the implementation of an LFE program on well-being and on an educational program in the NICU/PICU of a tertiary care center in France. METHODS: We created a workgroup composed of caregivers called the "3R team" for "right resuscitations reviews," based on the concept of AI. Before and 1 year after implementation, we administered two validated surveys-the Maslach Burnout Inventory and the Siegrist survey-to the entire staff of the 22-bed unit. RESULTS: The questionnaire on satisfaction revealed a high percentage (93%) of satisfaction with the work of the 3R team and that scores of well-being and burnout were improved. The educational program was highly enhanced, especially simulation. Benevolence and happiness were increased. CONCLUSION: Implementation of an LFE program in a NICU and PICU is feasible, and tends to increase the well-being and self-confidence of all categories of caregivers. It promotes educational programs of dynamic learning, including simulation. The next important step will be to study the impact on staff turnover and on quality of care.

Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Consensus of the Spanish society of laboratory medicine and the Spanish society of medical oncology on the methodology and criteria for evaluation of circulating tumour markers in breast cancer

The measurement of circulating tumour markers (TMs) for the diagnosis or monitoring of breast cancer has sometimes been considered of limited utility. In addition to the overinterpretation of irrelevant changes in marker levels, the characteristics of the patient, the disease or other pathologies that can modify them are often not considered in their evaluation. On the other hand, there are recent data on the relationship of TMs with molecular subtypes and on their prognostic value, the knowledge of which may improve their clinical utility. This consensus article arises from a collaboration between the Spanish Society of Laboratory Medicine (SEQCML) and the Spanish Society of Medical Oncology (SEOM). It aims to improve the use and interpretation of circulating TMs in breast cancer. The text summarizes the current knowledge and available evidence on the subject and proposes a series of recommendations mainly focussed on the indication, the frequency of testing and the factors that should be considered for correctly interpreting changes in the levels of TMs (AU)

Consensus of the Spanish society of laboratory medicine and the Spanish society of medical oncology on the methodology and criteria for evaluation of circulating tumour markers in breast cancer.

The measurement of circulating tumour markers (TMs) for the diagnosis or monitoring of breast cancer has sometimes been considered of limited utility. In addition to the overinterpretation of irrelevant changes in marker levels, the characteristics of the patient, the disease or other pathologies that can modify them are often not considered in their evaluation. On the other hand, there are recent data on the relationship of TMs with molecular subtypes and on their prognostic value, the knowledge of which may improve their clinical utility. This consensus article arises from a collaboration between the Spanish Society of Laboratory Medicine (SEQCML) and the Spanish Society of Medical Oncology (SEOM). It aims to improve the use and interpretation of circulating TMs in breast cancer. The text summarizes the current knowledge and available evidence on the subject and proposes a series of recommendations mainly focussed on the indication, the frequency of testing and the factors that should be considered for correctly interpreting changes in the levels of TMs.

Prefrontal-amygdala connectivity in trait anxiety and generalized anxiety disorder: Testing the boundaries between healthy and pathological worries.

BACKGROUND: Current brain-based theoretical models of generalized anxiety disorder (GAD) suggest a dysfunction of amygdala-ventromedial prefrontal cortex emotional regulatory mechanisms. These alterations might be reflected by an altered resting state functional connectivity between both areas and could extend to vulnerable non-clinical samples such as high worriers without a GAD diagnosis. However, there is a lack of information in this regard. METHODS: We investigated differences in resting state functional connectivity between the basolateral amygdala and the ventromedial prefrontal cortex (amygdala-vmPFC) in 28 unmedicated participants with GAD, 28 high-worriers and 28 low-worriers. We additionally explored selected clinical variables as predictors of amygdala-vmPFC connectivity, including anxiety sensitivity. RESULTS: GAD participants presented higher left amygdala-vmPFC connectivity compared to both groups of non-GAD participants, and there were no differences between the latter two groups. In our exploratory analyses, concerns about the cognitive consequences of anxiety (the cognitive dimension of anxiety sensitivity) were found to be a significant predictor of the left amygdala-vmPFC connectivity. LIMITATIONS: The cross-sectional nature of our study preclude us from assessing if functional connectivity measures and anxiety sensitivity scores entail an increased risk of GAD. CONCLUSIONS: These results suggest a neurobiological qualitative distinction at the level of the amygdala-vmPFC emotional-regulatory system in GAD compared to non-GAD participants, either high- or low-worriers. At this neural level, they question previous hypotheses of continuity between high worries and GAD development. Instead, other anxiety traits such as anxiety sensitivity might confer a greater proneness to the amygdala-vmPFC connectivity alterations observed in GAD.

RNA editing blood biomarkers for predicting mood alterations in HCV patients.

Treatment-emergent depression is a common complication in patients with chronic hepatitis C virus (HCV) infection undergoing antiviral combination therapy with IFN-α and ribavirin. It has recently been shown that changes in A-to-I RNA editing rates are associated with various pathologies such as inflammatory disorders, depression and suicide. Interestingly, IFN-α induces gene expression of the RNA editing enzyme ADAR1-1 (ADAR1a-p150) and alters overall RNA editing activity. In this study, we took advantage of the high prevalence of pharmacologically induced depression in patients treated with IFN-α and ribavirin to test the interest of RNA editing-related biomarkers in white blood cells of patients. In this 16-week longitudinal study, a small cohort of patients was clinically evaluated using standard assessment methods prior to and during antiviral therapy and blood samples were collected to analyse RNA editing modifications. A-I RNA editing activity on the phosphodiesterase 8A (PDE8A) gene, a previously identified RNA editing hotspot in the context of lupus erythematosus, was quantified by using an ultra-deep next-generation sequencing approach. We also monitored gene expression levels of the ADAR enzymes and the PDE8A gene during treatment by qPCR. As expected, psychiatric evaluation could track treatment-emergent depression, which occurred in 30% of HCV patients. We show that PDE8A RNA editing is increased in all patients following interferon treatment, but differently in 30% of patients. This effect was mimicked in a cellular model using SHSY-5Y neuroblastoma cells. By combining the data of A-I RNA editing and gene expression, we generated an algorithm that allowed discrimination between the group of patients who developed a treatment-emergent depression and those who did not. The current model of drug-induced depression identified A-I RNA editing biomarkers as useful tools for the identification of individuals at risk of developing depression in an objective, quantifiable biological blood test.

Assessment of Susceptibility Risk Factors for ADHD in Imaging Genetic Studies.

OBJECTIVE: ADHD consists of a count of symptoms that often presents heterogeneity due to overdispersion and excess of zeros. Statistical inference is usually based on a dichotomous outcome that is underpowered. The main goal of this study was to determine a suited probability distribution to analyze ADHD symptoms in Imaging Genetic studies. METHOD: We used two independent population samples of children to evaluate the consistency of the standard probability distributions based on count data for describing ADHD symptoms. RESULTS: We showed that the zero-inflated negative binomial (ZINB) distribution provided the best power for modeling ADHD symptoms. ZINB reveals a genetic variant, rs273342 (Microtubule-Associated Protein [MAPRE2]), associated with ADHD ( p value = 2.73E-05). This variant was also associated with perivascular volumes (Virchow-Robin spaces; p values < 1E-03). No associations were found when using dichotomous definition. CONCLUSION: We suggest that an appropriate modeling of ADHD symptoms increases statistical power to establish significant risk factors.

[Small cell lung cancer and immuno-oncologic agents: End of the cisplatin - etoposide era?] / Cancer bronchique à petites cellules et agent onco-immunologique : peut-on sortir de l'ère du tout cisplatine étoposide ?

In the setting of small cell lung cancer (SCLC), the development of immuno-oncological agents, particularly those targeting Programmed cell Death protein 1 (PD-1) and Programmed cell Death protein Ligand 1 (PD-L1), is still at an early stage. Two critical elements need to be considered : the current data are extracted from Phase I and Phase II trials and the level of evidence from phase III trials has not been reached as it has been for non-small cell lung cancer (NSCLC) or for malignant melanoma ; The second aspect is the slow development of predictive factors for response to the immuno-oncological agents targeting the PD-1 receptor and its ligand. The clinical data are still too fragmentary to produce recommendations, although the improvement in progression-free survival seen in different phase II studies is promising. The expectation of clinicians dealing withSCLC is an indication of the challenge that this disease currently poses to oncology and justifies a focused clinical research effort.

[What do chemotherapy specialists expect of lung cancer?] / Qu'attendent les médecins spécialistes de la chimiothérapie des cancers du poumon ?

OBJECTIVE: In an attempt to understand physicians' expectations of chemotherapy, a group of lung cancer specialists was involved in an online survey investigating their opinions by a self-questionnaire. The questionnaire described five different chemotherapy prescription situations for lung cancer patients (stages IIIB or IV). METHOD: A total of 30 expert specialists were invited; 22 responded (73%). For each of the clinical situations, the expert was asked for his opinion on 3 items: cure, prolongation of survival and alleviation of symptoms. Each item was judged on a Likert scale with categories between -2 "not at all probable" and +2 "quite likely". RESULTS: For "cure", the percentage of -2 responses differed significantly according to the clinical situation (Fisher test: P<0.00001). The trend test showed a relationship between the percentage of -2 responses and the suspected order of the clinical situations (Cochran-Armitage trend test: P<0.0001). For symptom alleviation, the percentage of responses +2 and +1 differed significantly according to the clinical situation (Fisher test: P=0.00013, trend test: P<0.0001). CONCLUSION: What specialist physicians expect of chemotherapy in terms of curability and symptom relief differs according to the actual statistical prognosis of each situation as presented in the literature. The worst prognostic situation leads to the strongest expectation in terms of symptom relief and, conversely, the lowest for curability.

Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder.

BACKGROUND: Pathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.AimsTo study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals. METHOD: In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging. RESULTS: Compared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety-threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC. CONCLUSIONS: Poor vmPFC safety-threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.Declaration of interestNone.

Assessment of brain activity during voluntary anal sphincter contraction: Comparative study in women with and without fecal incontinence.

BACKGROUND: Voluntary anal sphincter function is driven by an extended network of brain structures, most of which are still unknown. Disturbances in this function may cause fecal incontinence. The aim of this study was to characterize the cerebral areas involved in voluntary contraction of the anorectal sphincter in healthy women and in a group of patients with fecal incontinence by using a standardized functional magnetic resonance imaging (fMRI) protocol. METHODS: This comparative study included 12 healthy women (mean age 53.17 ± 4.93 years) and 12 women with fecal incontinence (56.25 ± 6.94 years). An MRI-compatible anal manometer was used to register voluntary external anal sphincter contraction. During brain fMRI imaging, participants were cued to perform 10-s series of self-paced anal sphincter contractions at an approximate rate of 1 Hz. Brain structures linked to anal sphincter contractions were mapped and the findings were compared between the 2 study groups. KEY RESULTS: There were no differences in the evoked brain activity between the 2 groups. In healthy women, group fMRI analysis revealed significant activations in medial primary motor cortices, supplementary motor area, bilateral putamen, and cerebellum, as well as in the supramarginal gyrus and visual areas. In patients with fecal incontinence, the activation pattern involved similar regions without significant differences with healthy women. CONCLUSIONS & INFERENCES: This brain fMRI-anorectal protocol was able to map the brain regions linked to voluntary anal sphincter function in healthy and women with fecal incontinence.

Systematic review with meta-analysis: neuroimaging in hepatitis C chronic infection.

BACKGROUND: Chronic hepatitis C is considered a systemic disease because of extra-hepatic manifestations. Neuroimaging has been employed in hepatitis C virus-infected patients to find in vivo evidence of central nervous system alterations. AIMS: Systematic review and meta-analysis of neuroimaging research in chronic hepatitis C treatment naive patients, or patients previously treated without sustained viral response, to study structural and functional brain impact of hepatitis C. METHODS: Using PRISMA guidelines a database search was conducted from inception up until 1 May 2017 for peer-reviewed studies on structural or functional neuroimaging assessment of chronic hepatitis C patients without cirrhosis or encephalopathy, with control group. Meta-analyses were performed when possible. RESULTS: The final sample comprised 25 studies (magnetic resonance spectroscopy [N = 12], perfusion weighted imaging [N = 1], positron emission tomography [N = 3], single-photon emission computed tomography [N = 4], functional connectivity in resting state [N = 1], diffusion tensor imaging [N = 2] and structural magnetic resonance imaging [N = 2]). The whole sample was of 509 chronic hepatitis C patients, with an average age of 41.5 years old and mild liver disease. A meta-analysis of magnetic resonance spectroscopy studies showed increased levels of choline/creatine ratio (mean difference [MD] 0.12, 95% confidence interval [CI] 0.06-0.18), creatine (MD 0.85, 95% CI 0.42-1.27) and glutamate plus glutamine (MD 1.67, 95% CI 0.39-2.96) in basal ganglia and increased levels of choline/creatine ratio in centrum semiovale white matter (MD 0.13, 95% CI 0.07-0.19) in chronic hepatitis C patients compared with healthy controls. Photon emission tomography studies meta-analyses did not find significant differences in PK11195 binding potential in cortical and subcortical regions of chronic hepatitis C patients compared with controls. Correlations were observed between various neuroimaging alterations and neurocognitive impairment, fatigue and depressive symptoms in some studies. CONCLUSIONS: Patients with chronic hepatitis C exhibit cerebral metabolite alterations and structural or functional neuroimaging abnormalities, which sustain the hypothesis of hepatitis C virus involvement in brain disturbances.

Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder.

BACKGROUND: The assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity. METHODS: Eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses. RESULTS: In comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus. CONCLUSIONS: This study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively.

Brain volumetric and metabolic correlates of electroconvulsive therapy for treatment-resistant depression: a longitudinal neuroimaging study.

Recent research suggests that neuroplastic and neuroinflammatory changes may account for the mode of action of electroconvulsive therapy (ECT), although extant data do not allow for a clear disambiguation between these two hypotheses. Multimodal neuroimaging approaches (for example, combining structural and metabolic information) may help in clarifying this issue. Here we aimed to assess longitudinal changes in (i) regional gray matter (GM) volumes and (ii) hippocampal metabolite concentrations throughout an acute course of bitemporal ECT, as well as (iii) to determine the association between imaging changes and clinical improvement. We assessed 12 patients with treatment-resistant depression (TRD) at four time points (pre-treatment, after the first ECT session, after the ninth ECT session and 15 days after ECT course completion) and 10 healthy participants at two time points, 5 weeks apart. Patients with TRD showed bilateral medial temporal lobe (MTL) and perigenual anterior cingulate cortex volume increases. Left MTL volume increase was associated with (i) a hippocampal N-acetylaspartate concentration decrease, (ii) a hippocampal Glutamate+Glutamine concentration increase and (iii) significant clinical improvement. The observed findings are, in part, compatible with both neuroplastic and neuroinflammatory changes induced by ECT. We postulate that such phenomena may be interrelated, therefore reconciling the neuroplasticity and neuroinflammatory hypotheses of ECT action.

Imaging of postoperative complications following surgery for lung cancer.

The complications following surgery for lung cancer vary depending upon the comorbidities and the type of surgery. Hemorrhage, infections and pulmonary edemas are not specific to the type of resection but frequently occur following pneumonectomies. Morbidity following pneumonectomies is related to the significant changes in the contents of the intrathoracic space. Pulmonary infarction and torsion are emergency situations that develop following lobectomy. CT shows features of localized congestion and stenosis or occlusion of a vein or bronchus. Rapid identification of severe events, in particular by systematic CT is essential for appropriate management of a postoperative or delayed complication of lung cancer surgery.

Interaction between airborne copper exposure and ATP7B polymorphisms on inattentiveness in scholar children.

Recent research indicates that airborne copper exposure in scholar children negatively affects brain functioning. These effects are likely to be influenced by the efficiency of copper metabolism, which is partly regulated by the ATPase copper transporting beta (ATP7B) gene. We investigated whether indoor and outdoor airborne copper exposure is differentially associated with child inattentiveness depending on genetic variation within the ATP7B gene in 1645 scholar children from the BREATHE project. Outdoor (courtyard) and indoor (classroom) air pollution levels were measured during class hours in each school. Inattentiveness was assessed through a follow-up with four measurements via the Attentional Network Test (4475 observations). Linear mixed models considering repeated measures were conducted to assess genetic and exposure main and interaction effects. Two interactions were detected indicating that ATP7B-rs1061472 (P for interaction 0.016) and ATP7B-rs1801243 (P for interaction 0.003) polymorphisms modified the association between indoor copper exposure and inattentiveness. Stratified analysis by genotypes revealed that both outdoor and indoor copper exposure increased inattentiveness in rs1061472-CC and rs1801243-CC carriers. These findings suggest that the genetic background promotes the association between airborne copper exposure at school with inattentiveness in children.