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Background In ARDS, the PEEP level associated with the best respiratory system compliance is often selected; however, intra-tidal recruitment can increase compliance, falsely suggesting improvement in baseline mechanics. Tidal lung hysteresis increases with intra-tidal recruitment and can help interpreting changes in compliance. This study aims to assess tidal recruitment in ARDS patients and to test a combined approach, based on tidal hysteresis and compliance, to interpret decremental PEEP trials. Methods A decremental PEEP trial was performed in 38 COVID-19 moderate to severe ARDS patients . At each step, we performed a low-flow inflation-deflation manoeuvre between PEEP and a constant plateau pressure, to measure tidal hysteresis and compliance. Results According to changes of tidal hysteresis, three typical patterns were observed: 10 (26%) patients showed consistently high tidal-recruitment, 12 (32%) consistently low tidal-recruitment and 16 (42%) displayed a biphasic pattern moving from low to high tidal-recruitment below a certain PEEP. Compliance increased after 82% of PEEP step decreases and this was associated to a large increase of tidal hysteresis in 44% of cases. Agreement between best compliance and combined approaches was accordingly poor (K = 0.024). The combined approach suggested to increase PEEP in high tidal-recruiters, mainly to keep PEEP constant in biphasic pattern and to decrease PEEP in low tidal-recruiters. PEEP based on the combined approach was associated with lower tidal hysteresis (92.7 ± 20.9 vs. 204.7 ± 110.0 mL; p  < 0.001) and lower dissipated energy per breath (0.1 ± 0.1 vs. 0.4 ± 0.2 J; p  < 0.001) compared to the best compliance approach. Tidal hysteresis ≥ 100 mL was highly predictive of tidal recruitment at next PEEP step reduction (AUC 0.97; p  < 0.001). Conclusions Assessment of tidal hysteresis improves the interpretation of decremental PEEP trials and may help limiting tidal recruitment and energy dissipated into the respiratory system during mechanical ventilation of ARDS patients.

The metabolic effects induced by antipsychotics in vitro depend on their action on the trafficking and biosynthesis of sterols and lipids. Previous research showed that antipsychotics with different adverse effects in patients cause similar alterations in vitro, suggesting the low clinical usefulness of cellular studies. Moreover, the inhibition of peripheral AMPK was suggested as potential aetiopathogenic mechanisms of olanzapine, and different effects on autophagy were reported for several antipsychotics. We thus assessed, in clinically-relevant culture conditions, the aetiopathogenic mechanisms of olanzapine, risperidone and ziprasidone, antipsychotics with respectively high, medium, low metabolic risk in patients, finding relevant differences among them. We highlighted that: olanzapine impairs lysosomal function affecting autophagy and autophagosome clearance, and increasing intracellular lipids and sterols; ziprasidone activates AMPK increasing the autophagic flux and reducing intracellular lipids; risperidone increases lipid accumulation, while it does not affect lysosomal function. These in vitro differences align with their different impact on patients. We also provided evidence that metformin add-on improved autophagy in olanzapine-treated cells and reduced lipid accumulation induced by both risperidone and olanzapine in an AMPK-dependent way; metformin also increased the production of bile acids to eliminate cholesterol accumulations caused by olanzapine. These results have different clinical implications. We demonstrated that antipsychotics with different metabolic impacts on patients actually have different mechanisms of action, thus supporting the possibility of a personalised antipsychotic treatment. Moreover, we found that metformin can fully revert the phenotype caused by risperidone but not the one caused by olanzapine, that still activates SREBP2.

Background Whether respiratory efforts and their timing can be reliably detected during pressure support ventilation using standard ventilator waveforms is unclear. This would give the opportunity to assess and improve patient–ventilator interaction without the need of special equipment. Methods In 16 patients under invasive pressure support ventilation, flow and pressure waveforms were obtained from proximal sensors and analyzed by three trained physicians and one resident to assess patient’s spontaneous activity. A systematic method (the waveform method) based on explicit rules was adopted. Esophageal pressure tracings were analyzed independently and used as reference. Breaths were classified as assisted or auto-triggered, double-triggered or ineffective. For assisted breaths, trigger delay, early and late cycling (minor asynchronies) were diagnosed. The percentage of breaths with major asynchronies (asynchrony index) and total asynchrony time were computed. Results Out of 4426 analyzed breaths, 94.1% (70.4–99.4) were assisted, 0.0% (0.0–0.2) auto-triggered and 5.8% (0.4–29.6) ineffective. Asynchrony index was 5.9% (0.6–29.6). Total asynchrony time represented 22.4% (16.3–30.1) of recording time and was mainly due to minor asynchronies. Applying the waveform method resulted in an inter-operator agreement of 0.99 (0.98–0.99); 99.5% of efforts were detected on waveforms and agreement with the reference in detecting major asynchronies was 0.99 (0.98–0.99). Timing of respiratory efforts was accurately detected on waveforms: AUC for trigger delay, cycling delay and early cycling was 0.865 (0.853–0.876), 0.903 (0.892–0.914) and 0.983 (0.970–0.991), respectively. Conclusions Ventilator waveforms can be used alone to reliably assess patient’s spontaneous activity and patient–ventilator interaction provided that a systematic method is adopted.

The RISKMet project aims to: (1) identify risk factors for metabolic syndrome (MetS) by comparing patients with and without MetS; (2) characterise patients treated with second-generation antipsychotics (SGAs) about MetS diagnosis; (3) study behavioural patterns, including physical activity (PA) and dietary habits, in patients and healthy individuals using a prospective cohort design. The RISKMet project investigates MetS in individuals treated with SGAs, focusing on both adult and paediatric populations. The study utilizes a case-control design to examine potential risk factors for MetS, categorizing participants as MetS+ considered as \"Cases\" and MetS- considered as \"Controls\" matched by sex and age. The evaluation of factors such as MetS, lifestyle habits, and environmental influences is conducted at two time points, T0 and T3, after 3 months. Subsequently, the project aims to assess body parameters, including physical examinations, and blood, and stool sample collection, to evaluate metabolic markers and the impact of SGAs. The analysis includes pharmacological treatment data and genetic variability. Behavioural markers related to lifestyle, eating behaviour, PA, and mood are assessed at both T0 and T3 using interviews, accelerometers, and a mobile app. The study aims to improve mental and physical well-being in SGA-treated individuals, establish a biobank for MetS research, build an evidence base for physical health programs, and develop preventive strategies for SGA-related comorbidities. This project innovates MetS monitoring in psychiatry by using intensive digital phenotyping, identifying biochemical markers, assessing familial risks, and including genetically similar healthy controls. ISRCTN18419418 at www.isrctn.com.

To evaluate epidemiological features of post vaccine acute disseminated encephalomyelitis (ADEM) by considering data from different pharmacovigilance surveillance systems. The Vaccine Adverse Event Reporting System (VAERS) database and the EudraVigilance post-authorisation module (EVPM) were searched to identify post vaccine ADEM cases. Epidemiological features including sex and related vaccines were analysed. We retrieved 205 and 236 ADEM cases from the EVPM and VAERS databases, respectively, of which 404 were considered for epidemiological analysis following verification and causality assessment. Half of the patients had less than 18 years and with a slight male predominance. The time interval from vaccination to ADEM onset was 2-30 days in 61% of the cases. Vaccine against seasonal flu and human papilloma virus vaccine were those most frequently associated with ADEM, accounting for almost 30% of the total cases. Mean number of reports per year between 2005 and 2012 in VAERS database was 40±21.7, decreasing after 2010 mainly because of a reduction of reports associated with human papilloma virus and Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B vaccines. This study has a high epidemiological power as it is based on information on adverse events having occurred in over one billion people. It suffers from lack of rigorous case verification due to the weakness intrinsic to the surveillance databases used. At variance with previous reports on a prevalence of ADEM in childhood we demonstrate that it may occur at any age when post vaccination. This study also shows that the diminishing trend in post vaccine ADEM reporting related to Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B and human papilloma virus vaccine groups is most likely not [corrected] due to a decline in vaccine coverage indicative of a reduced attention to this adverse drug reaction.

Background: Growing evidence supports a bidirectional association between diabetes and depression; promising but limited and conflicting data from human studies support the intriguing possibility that antidiabetic agents may be used to relieve effectively depressive symptoms in diabetic patients. We investigated the potential antidepressant effects of antidiabetic drugs in a high-scale population data from the two most important pharmacovigilance databases, i.e. , the FDA Adverse Event Reporting System (FAERS) and the VigiBase. Material and methods: From the two primary cohorts of patients treated with antidepressants retrieved from FDA Adverse Event Reporting System and VigiBase we identified cases (depressed patients experiencing therapy failure) and non-cases (depressed patients experiencing any other adverse event). We then calculated the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Empirical Bayes Regression-Adjusted Mean (ERAM) for cases versus non-case s in relation with the concurrent exposure to at least one of the following antidiabetic agent: A10BA Biguanides; A10BB Sulfonylureas; A10BG Thiazolidinediones; A10BH DPP4-inhibitors; A10BJ GLP-1 analogues; A10BK SGLT2 inhibitors ( i.e ., those agents for which preliminary evidence from literature supports our pharmacological hypothesis). Results: For GLP-1 analogues, all the disproportionality scores showed values <1, i.e. , statistically significant, in both analyses [from the FAERS: ROR confidence interval of 0.546 (0.450–0.662); PRR ( p -value) of 0.596 (0.000); EBGM (CI) of 0.488 (0.407–0.582); ERAM (CI) of 0.480 (0.398–0.569) and VigiBase: ROR (CI) of 0.717 (0.559–0.921); PRR ( p -value) of 0.745 (0.033); EBGM (CI) of 0.586 (0.464–0.733); ERAM of (CI): 0.515 (0.403–0.639)]. Alongside GLP-1 analogues, DPP-4 Inhibitors and Sulfonylureas showed the greatest potential protective effect. With regard to specific antidiabetic agents, liraglutide and gliclazide were associated with a statistically significant decrease in all disproportionality scores, in both analyses. Conclusion: The findings of this study provide encouraging results, albeit preliminary, supporting the need for further clinical research for investigating repurposing of antidiabetic drugs for neuropsychiatric disorders.

An amendment to this paper has been published and can be accessed via the original article.

Since the Middle Ages, human-powered tools and machines have played an important role in societies. Prominent among these are pedal-powered machines, which harness the overall power from the strongest muscles in the human body. The article identifies a historical taxonomy of pedal-powered machines to provide designers with an orientation map for devising new solutions, suggesting some contexts in which today’s pedal-powered machines can re-purpose ancient mechanisms to perform an innovative function. The reduction in energy consumption, the low environmental impact, and the autonomy of the process, in fact, can represent not only a technical rediscovery of engineering, but also a new way of supporting human subsistence.