Assessment of Neurologic Safety Profile of Immune Checkpoint Inhibitors: Evaluation of Adverse Drug Reaction Reports.

BACKGROUND: Immune checkpoint inhibitors (ICIs) used in immunotherapy have revolutionized cancer management. However, ICI therapy can come with serious neurologic risks. OBJECTIVE: The objective of our study is to analyze the occurrence of neurologic events with ICIs. METHODS: We referred to EudraVigilance (EV) and VigiAccess to evaluate the frequency of individual case safety reports (ICSRs), including neurologic events with ICIs. Data was gathered for a period from the date of ICI's marketing authorization till 30 January 2023. The computational assessment was conducted with the help of reporting odds ratio (ROR) and its 95% confidence interval (CI). RESULTS: Overall, 8181 ICSRs in EV and 15905 ICSRs from VigiAccess were retrieved for neurologic events, with at least one ICI as the suspected drug. The majority of the ICSRs were reported for nivolumab, pembrolizumab, and ipilimumab, whereas frequently reported events were neuropathy peripheral, myasthenia gravis, seizure, Guillain-Barre syndrome, paraesthesia, syncope, encephalopathy, somnolence. Under EV, 92% of ICSRs were reported as serious, 10% included fatal outcomes, and nearly 61% cited patient recovery. Atezolizumab (ROR 1.64, 95% CI 1.75- 1.52), cemiplimab (ROR 1.61, 95% CI 1.98-1.3), and nivolumab (ROR 1.38, 95% CI 1.44-1.31) had a considerable increase in the frequency of ICSR reporting. Cerebrovascular accident, posterior reversible encephalopathy syndrome, tremor, and somnolence were identified as potential signals. CONCLUSION: ICIs were significantly associated with neurologic risks, which cannot be generalized. A considerable increase in ICSR reporting frequency was observed with atezolizumab, cemiplimab, and nivolumab, while avelumab, pembrolizumab, durvalumab, and cemiplimab were linked with four potential signals. These findings suggest the consideration of a revision of the neurologic safety profile of ICIs. Furthermore, the necessity for additional ad-hoc research is emphasized.

The concentration of benzene, toluene, ethylbenzene, and xylene in ambient air of the gas stations in Iran: A systematic review and probabilistic health risk assessment.

Exposure to benzene, toluene, ethylbenzene, and xylene (BTEX) has been reported in gas stations. Exposure to BTEX can result in adverse health outcomes in workers such as cancer and neurological effects. The health risk assessments of exposure to BTEX could be useful in choosing suitable control measures. In this review, data from previous studies of gas station environments in Iran were collected from years 2000 to 2020. The health risk assessments were conducted through the estimation of cancer and noncancer risks using a Monte Carlo simulation based on the US Environmental Protection Agency method. The results showed that exposure to BTEX in some cities of Iran was greater than the occupational exposure limits. The results of cancer risk assessments demonstrated that cancer risk was not increased. However, results of noncancer risk assessments demonstrated that neurological toxicity from exposure to BTEX was significant in different cities of Iran. The health risk assessments indicated that workers at gas station are at health risk.

25th anniversary of the Berlin workshop on developmental toxicology: DevTox database update, challenges in risk assessment of developmental neurotoxicity and alternative methodologies in bone development and growth.

25 years after the first Berlin Workshop on Developmental Toxicity this 10th Berlin Workshop aimed to bring together international experts from authorities, academia and industry to consider scientific, methodologic and regulatory aspects in risk assessment of developmental toxicity and to debate alternative strategies in testing developmental effects in the future. Proposals for improvement of the categorization of developmental effects were discussed as well as the update of the DevTox database as valuable tool for harmonization. The development of adverse outcome pathways relevant to developmental neurotoxicity (DNT) was debated as a fundamental improvement to guide the screening and testing for DNT using alternatives to animal methods. A further focus was the implementation of an in vitro mechanism-based battery, which can support various regulatory applications associated with the assessment of chemicals and mixtures. More interdisciplinary and translation research should be initiated to accelerate the development of new technologies to test developmental toxicity. Technologies in the pipeline are (i) high throughput imaging techniques, (ii) models for DNT screening tests, (iii) use of computer tomography for assessment of thoracolumbar supernumerary ribs in animal models, and (iv) 3D biofabrication of bone development and regeneration tissue models. In addition, increased collaboration with the medical community was suggested to improve the relevance of test results to humans and identify more clinically relevant endpoints. Finally, the participants agreed that this conference facilitated better understanding innovative approaches that can be useful for the identification of developmental health risks due to exposure to chemical substances.

Using benchmark dose modeling for the quantitative risk assessment: Carbon nanotubes, asbestos, glyphosate.

Benchmark dose method is one of the most famous quantitative approaches available for toxicological risks prediction. However, it is not fully clear how occupational health professionals can use it for specific workplace scenarios requiring carcinogen risk assessment. The paper explores the hypothesis that benchmark dose method allows to effectively approximate dose-response data on carcinogenic response, providing reasonable estimations of risks in the situations when a choice between more complex models is not warranted for practical purposes. Three case studies were analyzed for the agents with different levels of scientific confidence in human carcinogenicity: carbon nanotubes, amosite asbestos, and glyphosate. For each agent, a critical study was determined, and a dose-response slope factor was quantified, based on the weighted average lower bound benchmark dose. The linear slope factors of 0.111 lifetime excess cases of lung carcinoma per mg/m3 of MWCNT-7 (in rats exposure equivalent), 0.009 cases of mesothelioma per f/cc-years of cumulative exposure to amosite asbestos, and 0.000094 cases of malignant lymphoma per mg/kg/day of glyphosate (in mice equivalent) were determined. The correlations between the proposed linear predictive models and observed data points were R = 0.96 (R2 = 0.92) for carbon nanotubes, R = 0.97 (R2 = 0.95) for amosite asbestos, and R = 0.89 (R2 = 0.79) for glyphosate. In all three cases, the linear extrapolation yielded comparable level of risk estimations with the "best fit" nonlinear model; for nanoparticles and amosite asbestos, linear estimations were more conservative. By performing a simulation study, it was demonstrated that a weighted average benchmark dose expressed the highest correlation with multistage and quantal-linear models.

Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma.

Importance: Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown. Objective: To estimate the economic differences in the administration of CAR T-cell therapy by the site of care and the incidence of key adverse events. Design, Setting, and Participants: A decision-tree model was designed to capture clinical outcomes and associated costs during a predefined period (from lymphodepletion to 30 days after the receipt of CAR T-cell infusion) to account for the potential incidence of acute adverse events and to evaluate variations in total costs for the administration of CAR T-cell therapy by site of care. Cost estimates were from the health care practitioner perspective and were based on data obtained from the literature and publicly available databases, including the Healthcare Cost and Utilization Project National Inpatient Sample, the Medicare Hospital Outpatient Prospective Payment System, the Medicare physician fee schedule, the Centers for Medicare and Medicaid Services Healthcare Common Procedure Coding System, and the IBM Micromedex RED BOOK. The model evaluated an average adult patient with relapsed or refractory large B-cell lymphoma who received CAR T-cell therapy in an academic inpatient hospital or nonacademic specialty oncology network. Intervention: The administration of CAR T-cell therapy. Main Outcomes and Measures: Total cost of the administration of CAR T-cell therapy by site of care. The costs associated with lymphodepletion, acquisition and infusion of CAR T cells, and management of acute adverse events were also examined. Results: The estimated total cost of care associated with the administration of CAR T-cell therapy was $454 611 (95% CI, $452 466-$458 267) in the academic hospital inpatient setting compared with $421 624 (95% CI, $417 204-$422 325) in the nonacademic specialty oncology network setting, for a difference of $32 987. After excluding the CAR T-cell acquisition cost, hospitalization and office visit costs were $53 360 (65.3% of the total cost) in academic inpatient hospitals and $23 526 (48.4% of the total cost) in nonacademic specialty oncology networks. The administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $29 834 (55.9%) decrease in hospitalization and office visit costs and a $3154 (20.1%) decrease in procedure costs. Conclusions and Relevance: The potential availability of CAR T-cell therapies that are associated with a lower incidence of adverse events and are suitable for outpatient administration may reduce the total costs of care by enabling the use of these therapies in nonacademic specialty oncology networks.

Effect of reduced use of organic solvents on disability pension in painters.

OBJECTIVE: To investigate whether the decreased use of paints based on organic solvents has caused a decreased risk for neuropsychiatric disorders in painters by studying their incidence in disability pensions. METHODS: The incidence of disability pension in Swedish painters who had participated in health examinations between 1971 and 1993 was studied through linkage with Swedish registers of disability pension over 1971-2010 and compared with the incidence in other construction workers as woodworkers, concrete workers and platers. When phasing out began in the 1970s, about 40% of paints were based on organic solvents and it had decreased to 4% in 1990s. The analysis was adjusted for age, time period, body mass index and smoking. RESULTS: The painters (n=23 065) had an increased risk of disability pension due to neurological diagnosis (n=285, relative risk (RR) 1.92, 95% CI 1.67 to 2.20) and psychiatric diagnosis (n=632, RR=1.61, 95 % CI 1.42 to 1.82). For neurological disorders there was a time trend with a continuously decreasing risk from 1980 onwards, but there was no such trend for psychiatric disorders. CONCLUSIONS: High exposure to organic solvents increased the risk for disability pension in neurological disorders, and the risk decreased when the use of organic solvents decreased. The painters also had an increased risk of disability pension due to psychiatric disorders, but the causes have to be further investigated.

How do smoking cessation medicines compare with respect to their neuropsychiatric safety? A protocol for a systematic review, network meta-analysis and cost-effectiveness analysis.

INTRODUCTION: Cigarette smoking is one of the leading causes of early death in the UK and worldwide. Public health guidance recommends the use of varenicline, bupropion and nicotine replacement therapy (NRT) as smoking cessation aids in the UK. Additionally, the first electronic cigarette has been licensed for use as a smoking cessation medicine. However, there are ongoing concerns about the safety of these medicines. We present a protocol for a systematic review and network meta-analysis (NMA) to determine how these smoking cessation medicines compare to each other with respect to their neuropsychiatric safety in adult smokers. Secondary aims include updating the evidence regarding the effectiveness and cardiovascular safety of these medicines for use in a cost-effectiveness analysis. METHODS AND ANALYSIS: We will include randomised controlled trials and observational studies with control groups comparing monotherapy with varenicline, bupropion, NRT or electronic cigarette and combination therapies to each other, placebo or usual care. The primary composite safety outcome will be serious adverse events, defined as events that resulted in death, were life threatening, required hospitalisation or resulted in significant disability or congenital/birth defect. The preferred effectiveness outcome will be sustained smoking cessation defined as abstinence for a minimum of 6 months as determined by biochemical validation. We will include trials identified by previous reviews and search relevant databases for newly published trials as well as contacting study authors to identify unpublished information. We will conduct fixed-effect and random-effect meta-analyses for each pairwise comparison of treatments and outcome; where these estimates differ, we will consider reasons for heterogeneity, quantified using the between-study variance (τ2). For each outcome, we will construct a NMA in a Bayesian framework which will be compared with the pair-wise results, allowing us to rank treatments. The effectiveness estimates from the NMA will be entered into a probabilistic economic model. ETHICS AND DISSEMINATION: Ethics approval is not required for this evidence synthesis study as it involves analysis of secondary data from randomised controlled trials and observational studies. The review will make an important contribution to the knowledge base around the effectiveness, safety and cost-effectiveness of smoking cessation medicines. Results will be disseminated to the general public, healthcare practitioners and clinicians, academics, industry and policy makers. PROSPERO REGISTRATION NUMBER: CRD42016041302.

Safety pharmacology investigations on the nervous system: An industry survey.

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

[ASSESSMENT OF THE CYTOKINE STATUS IN EMPLOYEES IN CONDITIONS OF CHRONIC EXPOSURE TO VINYL CHLORIDE].

In the article there are presented the results of the evaluation of cytokine profile in males working in the production of vinyl chloride (trained workers without signs of disorders of the neuropsychic status and persons with early signs of neurointoxication with vinyl chloride, characterized by asthenic (emotional lability) disorder with the autonomic dysfunction). There are established differences of pro- and anti-inflammatory responses in workers in dependence on the severity of disorders of the neuropsychic status. The most pronounced imbalance of cytokines was in workers with initial manifestations of neurointoxication with vinyl chloride. The increase in the concentration of pro-inflammatory cytokines (IL-1ß, IL-8, TNF-α) in trained employees without signs of disorders of the neuropsychic status is the one of the early and sensitive indices characterizing the formation ofthe body's resistance to exposure of adverse factors of production.

A global perspective on the influence of environmental exposures on the nervous system.

Economic transitions in the era of globalization warrant a fresh look at the neurological risks associated with environmental change. These are driven by industrial expansion, transfer and mobility of goods, climate change and population growth. In these contexts, risk of infectious and non-infectious diseases are shared across geographical boundaries. In low- and middle-income countries, the risk of environmentally mediated brain disease is augmented several fold by lack of infrastructure, poor health and safety regulations, and limited measures for environmental protection. Neurological disorders may occur as a result of direct exposure to chemical and/or non-chemical stressors, including but not limited to, ultrafine particulate matters. Individual susceptibilities to exposure-related diseases are modified by genetic, epigenetic and metagenomic factors. The existence of several uniquely exposed populations, including those in the areas surrounding the Niger Delta or north western Amazon oil operations; those working in poorly regulated environments, such as artisanal mining industries; or those, mostly in sub-Saharan Africa, relying on cassava as a staple food, offers invaluable opportunities to advance the current understanding of brain responses to environmental challenges. Increased awareness of the brain disorders that are prevalent in low- and middle-income countries and investments in capacity for further environmental health-related research are positive steps towards improving human health.

Assessment of emergency responders after a vinyl chloride release from a train derailment - New Jersey, 2012.

On November 30, 2012, at approximately 7:00 am, a freight train derailed near a small town in New Jersey. Four tank cars, including a breached tank car carrying vinyl chloride, landed in a tidal creek. Vinyl chloride, a colorless gas with a mild, sweet odor, is used in plastics manufacture. Acute exposure can cause respiratory irritation and headache, drowsiness, and dizziness; chronic occupational exposure can result in liver damage, accumulation of fat in the liver, and tumors (including angiosarcoma of the liver). Because health effects associated with acute exposures have not been well studied, the New Jersey Department of Health requested assistance from the Agency for Toxic Substances and Disease Registry (ATSDR) and CDC. On December 11, teams from these agencies deployed to assist the New Jersey Department of Health in conducting an assessment of exposures in the community as well as the occupational health and safety of emergency personnel who responded to the incident. This report describes the results of the investigation of emergency personnel. A survey of 93 emergency responders found that 26% of respondents experienced headache and upper respiratory symptoms during the response. A minority (22%) reported using respiratory protection during the incident. Twenty-one (23%) of 92 respondents sought medical evaluation. Based on these findings, CDC recommended that response agencies 1) implement the Emergency Responder Health Monitoring and Surveillance (ERHMS) system for ongoing health monitoring of the emergency responders involved in the train derailment response and 2) ensure that in future incidents, respiratory protection is used when exposure levels are unknown or above the established occupational exposure limits.

Compensation for occupational neurological and mental disorders.

Standards for the recognition of occupational diseases (ODs) in Korea were established in 1954 and have been amended several times. In 2013, there was a significant change in these standards. On the basis of scientific evidence and causality, the International Labour Organization list, European Commission schedule, and compensated cases in Korea were reviewed to revise the previous standards for the recognition of ODs in Korea. A disease-based approach using the International Classification of Diseases (10th version) was added on the previous standards, which were agent-specific approaches. The amended compensable occupational neurological disorders and occupational mental disorders (OMDs) in Korea are acute and chronic central nervous system (CNS) disorders, toxic neuropathy, peripheral neuropathy, manganese-related disorders, and post-traumatic stress disorder. Several agents including trichloroethylene (TCE), benzene, vinyl chloride, organotin, methyl bromide, and carbon monoxide (CO) were newly included as acute CNS disorders. TCE, lead, and mercury were newly included as chronic CNS disorders. Mercury, TCE, methyl n-butyl ketone, acrylamide, and arsenic were newly included in peripheral neuropathy. Post-traumatic stress disorders were newly included as the first OMD. This amendment makes the standard more comprehensive and practical. However, this amendment does not perfectly reflect the recent scientific progress and social concerns. Ongoing effort, research, and expert consensus are needed to improve the standard.

Longitudinal assessment of chlorpyrifos exposure and self-reported neurological symptoms in adolescent pesticide applicators.

OBJECTIVES: Occupational exposure of organophosphorus pesticides, such as chlorpyrifos (CPF), in adolescents is of particular concern because of the potential vulnerability of the developing neurological system. The objectives of this study were to examine how neurological symptoms reported over the application season vary across time, whether these effects are reversible postapplication and if there are associations between CPF biomarkers and neurological symptoms in an adolescent study population. SETTING: The longitudinal study was conducted in two agricultural districts of Menoufia Governorate, Egypt between April 2010 and January 2011. PARTICIPANTS: Male adolescent participants, including CPF applicators (n=57) and non-applicators (n=38), were recruited. PRIMARY AND SECONDARY OUTCOME MEASURES: Self-reported data for 25 neurological symptoms were collected at 32 time points over the 8-month period before, during and after the application season. Additionally, urine and blood samples were collected to measure urine trichloro-2-pyridinol (TCPy), a CPF-specific biomarker and blood cholinesterase activity. RESULTS: Applicators and non-applicators report the highest numbers of symptoms during the application season, followed by a reduction in symptoms after the application ended. Applicators reported a greater percentage of neurological symptoms, relative to baseline, than non-applicators after accounting for potential covariates. Among the applicators, cumulative TCPy was positively and significantly associated with the average percentage of symptoms (B=4.56, 95% CI 3.29 to 5.84; p<0.001). Significant associations (p=0.03-0.07) between the change in butyrylcholinesterase activity from the preapplication to the postapplication season and several domains of neurological symptoms were also found, even after adjusting for potential covariates. CONCLUSIONS: These observations demonstrate changes in the reporting of symptoms across the application season, showing an increase in symptom reporting during application and recovery following the end of pesticide application. These findings reinforce the growing concern regarding the neurotoxic health effects of CPF in adolescent applicators in developing countries and the need for developing and implementing intervention programmes.

Toxicological assessment of drugs that affect the endocrine system in puberty-related disorders.

INTRODUCTION: Toxicologists must ensure that clinical risk-to-benefit analysis should be made both for genders and age groups, with any treatment. Puberty concerns physiological changes leading to organism's maturation. Pubertal growth disorders are increasing in last decades: besides causing physical and psychological distress, they may signal underlying endocrine-metabolic abnormalities with serious health consequences later on. Therapeutic approaches for some health conditions in childhood and adolescence are considered. AREAS COVERED: The authors discuss how some diseases and treatments can impact pubertal growth. The authors look at particular immunological disorders such as asthma and how both the disease and treatment affects pubertal growth. They also discuss how the provision of available data can help to assess the dose-response of the drug, in these cases, and minimize the chance of side effects. The authors also discuss pediatric inflammatory bowel disease and how both the disease and treatment can mitigate the growth delay. Last, but not least, the authors discuss how the effects of the drugs used in the treatment of psychiatric disorders may accentuate endocrine issues in juvenile patients. Hyperprolactinemia induction by some antipsychotics is highlighted as an example. EXPERT OPINION: Appropriate risk-benefit analysis of drugs prescribed during childhood and adolescence and intended to be used in the long term is required. Furthermore, future treatment strategies and safer compounds development should be supported by the knowledge of mechanisms underlying adverse side effects in pubertal growth and development.

Risk trade-offs in fish consumption: a public health perspective.

Fish consumption advisories instruct vulnerable consumers to avoid high mercury fish and to limit total fish intake to reduce neurotoxic risk. Consumption data from the U.S. suggest that nontarget consumers also respond to such advice. These consumers reduce exposure to mercury and other toxicants at the cost of reduction in cardioprotective fatty acids. We present a probabilistic model to assess these risk trade-offs. We use NHANES consumption data to simulate exposure to contaminants and nutrients in fish, employ dose-response relationships to convert exposure to health end points, and monetize them using benefit transfer. Our results suggest that newborns gained on average 0.033 IQ points from their mothers' compliance with the prominent FDA/EPA advisory. The welfare gain for a birth cohort is estimated at $386 million. This gain could be fully offset by increments in cardiovascular risk if 0.6% of consumers aged 40 and older reduced fish intake by one monthly meal until they reached the age of 60 or if 0.1% of them permanently reduced fish intake.

Pediatric anesthesia and neurodevelopmental impairments: a Bayesian meta-analysis.

Experimental evidence of anesthesia-induced neurotoxicity has caused serious concern about the long-term effect of commonly used volatile anesthetic agents on young children. Several observational studies based on existing data have been conducted to address this concern with inconsistent results. We conducted a meta-analysis to synthesize the epidemiologic evidence on the association of anesthesia/surgery with neurodevelopmental outcomes in children. Using Bayesian meta-analytic approaches, we estimated the synthesized odds ratios (OR) and 95% credible interval (CrI) as well as the predictive distribution of a future study given the synthesized evidence. Data on 7 unadjusted and 6 adjusted measures of association were abstracted from 7 studies. The synthesized OR based on the 7 unadjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.9 (95% CrI, 1.2-3.0). The most likely unadjusted OR from a future study was estimated to be 2.2 (95% CrI, 0.6-6.1). The synthesized OR based on the 6 adjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.4 (95% CrI, 0.9-2.2). The most likely adjusted OR from a future study was estimated to be 1.5 (95% CrI, 0.5-4.0). We conclude that existent epidemiologic evidence suggests a modestly elevated risk of adverse behavioral or developmental outcomes in children who were exposed to anesthesia/surgery during early childhood. The evidence, however, is considerably uncertain.

[Identifying and prioritising adverse episodes and failures related to patient safety in Pain Treatment Units]. / Identificación y priorización de episodios adversos y fallos relacionados con la seguridad del paciente en las Unidades de Tratamiento del Dolor.

OBJECTIVES: An expert group coordinated by the Andalusian School of Public Health identified the most serious and frequent adverse events in Pain Treatment Units (PTU), as well the failures and underlying causes, as a prior step to preparing preventive actions. The aims of the project were to identify potential adverse events in Pain Treatment Units, identify failures and their underlying causes, and prioritise these failures according to a failure modes and effects analysis (FMEA) tool. MATERIAL AND METHODS: The method employed consisted of a literature search, the selection of an expert group with experience in PTU, creating a catalogue of adverse events using the generation of ideas technique, and putting the FMEA and Risk Priority Index tools into practice. RESULTS: Up to 66 types of adverse events were identified associated with; medication (30), invasive techniques (15), care process (10), patient information and education (6), and clinical practice (5). It was found that up to 101 failures could be triggered by these adverse events, and that 242 causes could lead to these failures. CONCLUSIONS: The results indicated the need to work principally in two directions, improving the care process in the PTU (the health care organisation), and the professional work, this latter having two aspects, improving the clinical practice, and increase professional skills by means of specific training. Communication, whether inter-professional or inter-department, or with the patient and their family, is identified as a key aspect for improvement.