IL-4/13 Blockade and sleep-related adverse drug reactions in over 37,000 Dupilumab reports from the World Health Organization Individual Case Safety reporting pharmacovigilance database (VigiBase™): a big data and machine learning analysis.

OBJECTIVE: Atopic dermatitis displays a relevant sleep burden sustained by clinical (i.e., itch), psychological (i.e., inadequate coping strategies) and therapeutic (i.e., frequent loss of drug response) triggers. Dupilumab, the first biologic approved for atopic dermatitis, showed excellent effects on improving pruritus and sleep after only two weeks of treatment but, in some cases, may have paradoxical effects. The rate of sleep-related side-effects remains unknown. More specifically, adverse-drug reactions (ADRs) related to dupilumab have been investigated during the safety phase of randomized clinical trials or in small retrospective epidemiological surveys, but little is known about sleep-related ADRs in real-life settings. Therefore, we took advantage of a global large-scale pharmacovigilance database, carrying out a comprehensive data mining analysis to look at different sleep-related ADRs reported among patients under anti IL-4/13 therapy. MATERIALS AND METHODS: We analyzed individual case study reports (ICSRs) in VigiBaseTM, the World Health Organization (WHO) global pharmacovigilance database of ADRs collected by national drug authorities in > 140 countries (> 90% of the world population). We looked for patterns of potentially sleep-related ADRs and we applied a disproportionality analysis based on Bayesian Confidence Propagation Neural Network (BCPNN). A meta-analytical approach was used to synthesize the overall effect size of sleep-related ADRs potentially associated to Dupilumab administration. RESULTS: From inception up to March 9, 2021, 94,065 ADRs from 37,848 unique reports were included and analyzed in the present paper: 1,294 of them (1.4%) concerned sleep disturbances (n=27). Most of sleep-related complaints were generic sleep disorders (n=630), followed by insomnia (n=312), somnolence (n=81), lethargy (n=60), night sweats (n=30), middle insomnia (n=39), hypersomnia (n=25), poor-quality sleep (n=21), initial insomnia (n=17), sleep apnea syndrome (n=13), nightmares (n=11) and sleep deficit (n=11). Interestingly, restlessness and restless leg syndrome, nocturnal dyspnea, narcolepsy and bruxism were reported in 7, 6, 5, 4 and 3 cases, respectively. Only sleep deficit [OR 15.67 (95% CrI 8.61-28.51); IC 3.24 (95% CrI 2.26-3.97)], generic sleep disorder [OR 6.22 (95% CrI 5.74-6.73); IC 2.60 (95% CrI 2.48-2.71)], nocturnal dyspnea [OR 3.68 (95% CrI 1.53-8.87); IC 1.56 (95% CrI 0.03-2.56)] and middle insomnia [OR 1.87 (95% CrI 1.36-2.56); IC 0.88 (95% CrI 0.39-1.30)] achieved the statistical significance threshold. CONCLUSIONS: In this work, we identified over 37,000 unique case-reports of Dupilumab side-effects reported on the WHO pharmacovigilance database. We specifically categorized those related to sleep issues, which were 1,294. Our findings from large numbers of cases provide data supporting the clinical observations that Dupilumab is usually effective in improving sleep quality and sleep disturbances/impairments, given the lack of statistical significance of several sleep-related ADRs. Further work is needed to closely scrutinize the impact of Dupilumab on sleep, in terms of underlying mechanisms, and to better understand residual sleep disorders in patients with atopic dermatitis and other allergic diseases treated with Dupilumab. Thus, sleep monitoring may be helpful for dermatologists in managing atopic dermatitis patients treated with dupilumab. The limitations of spontaneous reporting systems including underreporting and reporting bias, heterogeneity of sources and impossibility to infer any causal relationship merit consideration and further research is needed.

Psoriatic and psoriatic arthritis patients with and without jet-lag: does it matter for disease severity scores? Insights and implications from a pilot, prospective study.

Background: Jet-lag may affect air-travelers crossing at least two time-zones and has several health-care implications. It occurs when the human biological rhythms are out of synch with respect to the day-night cycle at the country destination. Its effect in psoriasis is missing. We aimed to evaluate the effect of Jet-lag in psoriatic patients' management. Methods: This is a prospective observational study that enrolled psoriatic patients that underwent a flight: patients who experienced jet-lag were compared to patients who did not experience jet-lag. Before the flight, a dermatologist recorded clinical and demographical data with particular attention to Psoriasis Area Severity Index (PASI) and Disease Activity in Psoriatic Arthritis (DAPSA). Patients performed Self-Administered Psoriasis Area Severity Index (SAPASI), the Dermatology Life Quality Index (DLQI) and the pruritus Visual Analog Scale (VAS) scores. After the flight, patients completed the SAPASI, DLQI and pruritus-VAS scores. Results: The sample recruited comprised of 70 psoriatic patients aged 42.4 ± 9.7 years (median 42.5 years). Thirty (42.9%) were males, mean BMI was 25.5 ± 2.2 kg/m2. Average disease duration was 15.2 ± 7.1 years, and 20 (28.6%) subjects had developed PsA. Average hours of flight were 5.4 ± 3.5 (median 3.5 h), with 34 (48.6%) subjects reporting jet-lag. At the multivariate regression analysis, the change in the SAPASI score resulted correlated with jet-lag (regression coefficient 1.63, p = .0092), as well the change in the DLQI score (regression coefficient = 1.73, p = .0009), but no change on the pruritus VAS scale was found. Conclusions: The present study suggests that jet-lag may influence disease severity and DLQI scores, but not itch in psoriatic patients.

Work-related stress as a cardiovascular risk factor in police officers: a systematic review of evidence.

PURPOSE: Several studies suggest that work-related stress in police officers may be associated with an increased risk of cardiovascular diseases. A systematic review of studies is, however, still lacking. METHOD: According to PRISMA statement, a systematic search of PubMed, ISI Web of Science, Cinahl and PsychInfo electronic databases was undertaken. Studies published in English between 1/1/2000 and 31/12/2016 were included. A studies quality assessment was performed using the Newcastle Ottawa scale (NOS). RESULTS: The preliminary search retrieved 752 records. After selection, 16 studies (total population 17,698) were retrieved. The average quality of studies was low. Exposure to stress in cross-sectional studies was inconstantly associated with hypertension, obesity, dyslipidaemia, and impaired glucose metabolism. In addition, there was a prevalence of positive studies showing an association between stress and cardiovascular disease morbidity. Studies of higher quality, such as longitudinal studies on large sample size, were more supportive of a significant positive association between stress and cardiovascular risk factors. Results were, however, often conflicting and inconsistent with regard to definitions and measurement of stress, features of individual study design, study conduct, and conclusions drawn. CONCLUSIONS: A sound precautionary principle would be to adopt worksite health promotion programs designed to implement stress management strategies in this category of workers.

Occupational Medicine and Hygiene: applied research in Italy.

The goal of Occupational Medicine and Hygiene is that of ensuring safety, health and well-being at workplaces, mainly assessing and preventing existing occupational risks. Scientific research in this field can provide useful arguments and further evidence upon which effective, efficient and sustainable policies and preventive measures have to be chosen and applied by the occupational physician in work-life. This paper summarizes four original studies, conducted in different professional settings across Italy, focusing on critical items, such as stress and violence, biological risks and sleep hygiene. The knowledge obtained can be useful to orientate proper preventive programs aimed at improving workplace health.

[Alcohol and work. Consensus Document of the La.R.A. (Workers representing a risk for others) group]. / Alcol e Lavoro. Documento di consenso del gruppo La.R.A.

AIM: Current Italian legislation obliges employers to prevent workers who are occupationally at risk or who perform jobs that may be hazardous for the safety or health of third parties from consuming alcohol. The LaRA Group undertook to assess whether the law fully safeguards the health and safety of both workers and third parties, without impinging upon the civil rights of workers. METHOD: A written document expressing agreement was produced following discussions between doctors, lawyers, bioethicists and social partners. RESULTS: There are gaps and inconsistencies in current laws; the differences in local and regional provisions prevent authorities from applying a single strategy at national level. There should be a change in existing rules under which the employer's obligation to enforce the ban on consumption alcohol in the workplace is enacted solely by the "competent" physician whose institutional role is to safeguard and promote health. Some occupational categories that are subject to a ban on alcohol consumption do not currently under-go health surveillance. For example, if road transport drivers are not exposed to a specific occupational risk foreseen under another law, they can be placed under health surveillance only in those regions where the local laws contemplate this type of control. In other cases, the practice of assessing the risk to third parties and providing for compulsory health surveillance in the Risk Assessment Document, is considered by some jurists to be a "consuetudo praeter legem" and therefore acceptable in a field not yet covered by a specific law, but to be "contra legem" or unlawful by other jurists. Moreover, the competent physician who uses a breathanalyser or tests for alcohol addiction faces an ethical dilemma, since by communicating the results to an employer or authorities responsible for the issuing of licenses, he may be violating his professional oath of secrecy. Furthermore, the emphasis placed on testing has induced companies and inspectors to overlook educational and rehabilitation aspects. It is essential to involve general practitioners, educators and specialist services in addressing the problems of alcohol abuse so as to inform/train, recover and rehabilitate. The few studies available indicate that the rules are poorly enforced and that non-compliance may go unobserved. CONCLUSIONS: The Group urges all employers to assess the risk for third parties caused by alcohol abuse and to devise a policy on alcohol. Controlling alcohol-related risks in the workplace calls for a better definition of the roles of Vigilance Bod-ies and Company Physicians together with a shift from a reactive to a proactive attitude of all the parties involved.

A novel description of FDG excretion in the renal system: application to metformin-treated models.

This paper introduces a novel compartmental model describing the excretion of 18F-fluoro-deoxyglucose (FDG) in the renal system and a numerical method based on the maximum likelihood for its reduction. This approach accounts for variations in FDG concentration due to water re-absorption in renal tubules and the increase of the bladder's volume during the FDG excretion process. From the computational viewpoint, the reconstruction of the tracer kinetic parameters is obtained by solving the maximum likelihood problem iteratively, using a non-stationary, steepest descent approach that explicitly accounts for the Poisson nature of nuclear medicine data. The reliability of the method is validated against two sets of synthetic data realized according to realistic conditions. Finally we applied this model to describe FDG excretion in the case of animal models treated with metformin. In particular we show that our approach allows the quantitative estimation of the reduction of FDG de-phosphorylation induced by metformin.

Personality traits of the Five-Factor Model are associated with work-related stress in special force police officers.

PURPOSE: The police work is particularly stressful. The aim of this work was to clarify whether the personality factors are associated with perceived stress levels or reactivity to environmental stressors in a special body of police. METHODS: The police officers in charge of guaranteeing public order at the L'Aquila G8 meeting were subjected to a control of their levels of work-related stress in anticipation of the event. Personality was assessed by the Italian version of the Five-Factor Model questionnaire, while stress was measured three times (during routine work in January 2009, preparation and imminence of the event, in April and July 2009, respectively) with the demand/control/support model of Karasek and the effort/reward imbalance model of Siegrist. A total of 289 of 294 officers took part in the survey. RESULTS: Some personality traits of the Five-Factor Model were associated with stress levels and stress reactivity. Neuroticism (low emotional stability) showed the strongest associations with job strain (demand/control ratio) (ß = 0.115, p < 0.05) and effort/reward imbalance (ß = 0.270, p < 0.001) and was associated with most of the stress variables. High agreeableness was associated with low effort/reward imbalance (ß = -0.157, p < 0.01). CONCLUSIONS: Personality factors may mitigate or increase the strain induced by environmental stressors.

[Sleep disorders and work: guidelines for health surveillance, risk management and prevention]. / I disturbi del sonno in ambito lavorativo: indirizzi di sorveglianza sanitaria, prevenzione e gestione del rischio.

Sleep disorders and related diseases are becoming increasingly relevant for the health and wellbeing of the general and working populations. Sleep disorders affect all aspects of health, showing a bi-directionality with health conditions and comorbidity with several diseases. Consequently, sleep disorders may have severe negative consequences both for the individual and the enterprise, as well as for society on the whole, in terms of health, productivity and social costs. When considering the disturbances of the sleep/wake cycle, it is important to distinguish between those connected with endogenous biological factors from those related to socio-environmental conditions, including work, and those associated with mental and physical diseases, that are often associated and interact with each other. Many sleep disorders are still underestimated and under-valued in clinical practice and, to a much greater extent, in workers' health surveillance. The present paper is aimed at drawing the attention of the occupational health physician to some key issues, particularly regarding excessive daytime sleepiness, obstructive sleep apnea syndrome and shift and night work, as well as their implications in terms of health and occupational consequences. Information on the main aspects of clinical diagnosis and health surveillance, as well as risk management and prevention at the workplace, are provided.

[Sleep, stress, neurogenesis and driving performance]. / Sonno, stress, neurogenesi e performance alla guida.

The enormous number of traffic accidents, implying a firm place in the top three death-rate causation in most industrialised countries, has inspired the development of studies of its major cause, i.e. human behaviour. Many traffic accidents are caused by, or at least related to, inadequate mental workload and, when it is either too low (vigilance, sleepiness) or too high (stress). Poor or inadequate sleep is a frequent result of being "stressed out." Professional and commuter drivers suffering from both daytime sleepiness and stress, two main factors impairment road safety mediated by behaviours including cognitive lapses, errors, and intentional traffic violations. Previous research has shown the association between stress or excessive daytime sleepiness and crash involvement but they never considered their linkage and their similar brain action: the hippocampus, amygdala, and prefrontal cortex undergo stress or poor or inadequate sleep induced structural remodelling (neuroplasticity and neurogenensis), which alters behavioral and physiological responses which can be either adaptive or damaging.

[Sleepiness, safety on the road and management of risk]. / Eccessiva sonnolenza e rischio infortunistico alla guida.

Public health studies have shown that sleepiness at the wheel and other risks associated with sleep are responsible for 5% to 30% of road accidents, depending on the type of driver and/or road. In industrialized countries one-fifth of all traffic accidents can be ascribed to sleepiness behind the wheel. Sleep disorders and various common acute and chronic medical conditions together with lifestyles, extended work hours and prolonged wakefulness directly or indirectly affect the quality and quantity of one's sleep increasing the number of workers with sleep debt and staggered hours. These conditions may increase the risk of road accidents. Strategies to reduce this risk of both commercial and non-commercial drivers related to sleepiness include reliable diagnosis and treatment of sleep disorders, management of chronobiological conflicts, adequate catch-up sleep, and countermeasures against sleepiness at the wheel. Road transport safety requires the adoption of occupational health measures, including risk assessment, health education, technical-environmental prevention and health surveillance.

[Obstructive sleep apnea syndrome in bus drivers: clinical and polysomnographic study]. / Sindrome delle apnee ostruttive nel sonno in guidatori di autobus: uno studio clinico e polisonnografico.

A Questionnaire on sleep and vigilance disorders has been developed by the Italian Association of Sleep Medicine to help the occupational health physicians in screening for sleep disorders. Aim of this study was to compare the Questionnaire with standardized questionnaires for sleepiness and sleep apnea and with a polysomnographic evaluation. Four hundred sixty-three (463#) commercial bus drivers (454M, 9F; mean age +/- S.D. 41.6 +/- 8.1 yrs; mean body mass index 26.2 +/- 3.6 kg/m2) underwent clinical evaluation that included the Italian Association of Sleep Medicine Questionnaire on sleep and vigilance disorders and two standardized questionnaires (Berlin Questionnaire and Epworth Sleepiness Scale). According to the Italian Association of Sleep Medicine Questionnaire on sleep and vigilance disorders 40 subjects presented an high risk for sleep disturbance and in 28 subject the questionnaires were concordant. Preliminary results (16 patients) showed an high rate of concordance between questionnaire and PSG. These data strongly suggest that sleep disorders and symptoms, that are frequent in a population of professional bus drivers, should be better evaluated during occupational health visit.

Police job strain during routine activities and a major event.

BACKGROUND: Special police forces are exposed to periods of intense work stress in ensuring public order. AIMS: To explore the relationship between the work context (routine work or special event) of special force policemen and psychological measures of job strain (demand-control) and effort-reward imbalance. METHODS: All policemen assigned to the G8 meeting in L'Aquila, Italy, in July 2009 were invited to complete a questionnaire while engaged in routine work in January 2009 (Time A) and in June 2009 (Time B), while preparing for the special event. RESULTS: Participation rate in the questionnaire study was 292/294 (99%) members of the special police force. Measures of job strain (-0.39, P < 0.001) and effort-reward imbalance (-0.37, P < 0.001) decreased significantly from Time A to Time B. On average, demand decreased from 14.2 ± 1.9 to 12.6 ± 2.7 (P < 0.001), control increased from 11.8 ± 2.5 to 14.4 ± 3.4 (P < 0.001) and social support increased from 17.8 ± 2.9 to 19.0 ± 3.1 (P < 0.001). At the same time, effort decreased from 17.4 ± 3.2 to 11.8 ± 3.8 (P < 0.001), reward grew from 37.6 ± 5.5 to 45.5 ± 7.4 (P < 0.001) and overcommitment dropped from 7.1 ± 2.1 to 6.6 ± 1.7 (P < 0.001). CONCLUSIONS: In special police forces, routine work may be significantly more stressful than a single critical event.

[The coping and support activities in the phenomenon of mass immigration in Italy: evaluation of work-related stress in police forces]. / L'attività di accoglienza e sostegno nel fenomeno di immigrazione di massa in Italia: valutazione dello stress lavoro-correlato nelle Forze di Polizia.

UNLABELLED: The recent emergence of new democracies in North Africa results in a massive wave of immigration in Europe with thousands landing in recent months on the coast of southern Italy. This phenomenon has caused major problems of public order (PO), worsened by the presence of ever-increasing numbers of immigrants and multiculturalism, exposing the Special Forces of the Italian State Police in periods of intense work-related stress. AIMS: To explore the relationship between work context (OP routine i.e. mass migration control vs. OP extraordinary i.e. the G8 summit) of special force policemen and psychological measures of job strain (demand-control, JCQ and effort-reward imbalance, ERI) related to objective measure (sickness absences). CONCLUSIONS: data showed that in special police forces routine work as migration control is significantly more stressful than a single special event that presents a very high risk for law enforcement, probably due to positive changes in psychosocial work environment among special police force.

[Guidelines for the fitness to drive assessment in people with obstructive sleep apnoea syndrome (OSAS) and narcolepsy]. / Linee guida per l'accertamento dell'idoneità alla guid in soggetti affetti da Sindrome delle apnee ostruttive del sonno (OSAS) e Narcolessia.

Given the prevalence of sleep disorders and sleep deprivation in modern societies, and the correlation between sleepiness and work and driving accidents, the excessive daytime sleepiness is an important issue. Although many studies showed that patients with untreated Obstructive sleep apnoea syndrome (OSAS) and narcolepsy have an higher risk for driving accidents, neither the European Community regulation nor the Italian law of the driving licence mention restrictions for these disorders. In 2010 the scientific association COMLAS (Association of legal medicine professionals of the Italian National Health Service) published the Guidelines for the examination by the Local Medical Commissions. The author presented the guidelines to assess the fitness to drive of people with OSAS or narcolepsy. The proposed criteria, set up in collaboration with the Commission "Sleepiness, Safety and Transportation" of the Italian Association of Sleep Medicine (AIMS), can be considered among the most advanced internationally.

[Sleepiness, sleep disorders and risk of occupational accidents]. / Sonnolenza, disturbi del sonno e rischio infortunistico.

Sleepiness, a commonly symptom affecting up to one-fifth of the population chronically, is clearly an important cause of accidents in industry and transport inducing deterioration in performance and attention. The reason for Excessive Daytime Sleepiness (EDS) is either sleep pathology, voluntary (non-pathological) sleep reduction, or activity during the circadian low. Most of the professional accidents reported refer to the obstructive sleep apnea syndrome (OSAS). Our data confirmed higher prevalence of OSAS in truck drivers than general population and we elaborated a feasible screening tool for OSAS based on data by clinical and anthropometric variables, some items of Sleep Disorders Score and complete polysomnography. About commuting accidents (CA) in shift and non shift workers we found a strict significant relationship between shift-work condition and the presence of EDS (p < 0.0001) suggesting that CA are significantly influenced by ED in the hypothesis of disruption of the balance between circadian and homeostatic factors in shift work. In conclusion to improve safety in the workplace a standardized procedure to evaluate risks a work should be developed based on epidemiological and experimentalffindings focused on EDS.

[Influence of environmental discomfort on musculoskeletal disorders]. / Influenza dei fattori ambientali sui disturbi muscoloscheletrici.

Musculoskeletal disorders (MSDs) are common among hospital workers. This cross-sectional study on 1744 hospital workers showed strong interaction between temperature complaints (OR 2.73), other environmental complaints (OR 3.12) and upper limbs disorders. A significant interaction between temperature and strain for upper limbs disorders (F = 9.52, p = 0.023) was also found. Environmental and psychosocial factors can interact increasing significantly the risk of MSDs.

Periodic limb movements both in non-REM and REM sleep: relationships between cerebral and autonomic activities.

OBJECTIVE: To investigate the temporal relationship between cerebral and autonomic activities before and during periodic limb movements in NREM and REM sleep (PLMS). METHODS: Patterns of EEG, cardiac and muscle activities associated with PLMS were drawn from polysomnographic recordings of 14 outpatients selected for the presence of PLMS both in NREM and REM sleep. PLMS were scored during all sleep stages from tibial EMG. Data from a bipolar EEG channel were analyzed by wavelet transform. Heart rate (HR) was evaluated from the electrocardiogram. EEG, HR and EMG activations were detected as transient increase of signal parameters and examined by analysis of variance and correlation analysis independently in NREM and REM sleep. Homologous parameters in REM and NREM sleep were compared by paired t-test. RESULTS: The autonomic component, expressed by HR increase, took place before the motor phenomenon both in REM and NREM sleep, but it was significantly earlier during NREM. In NREM sleep, PLM onset was heralded by a significant activation of delta-EEG, followed by a progressive increase of all the other bands. No significant activations of delta EEG were found in REM sleep. HR and EEG activations positively correlated with high frequency EEG activations and negatively (in NREM) with slow frequency ones. CONCLUSIONS: Our findings suggested a heralding role for delta band only in NREM sleep and for HR during both NREM and REM sleep. Differences in EEG and HR activation between REM and NREM sleep and correlative data suggested a different modulation of the global arousal response. SIGNIFICANCE: In this study, time-frequency analysis and advanced statistical methods enabled an accurate comparison between brain and autonomic changes associated to PLM in NREM and REM sleep providing indications about interaction between autonomic and slow and fast EEG components of arousal response.