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Critical illness myopathy (CIM) detrimentally affects muscle function in ICU patients, with a dramatic loss of muscle mass and function where the loss in specific force exceeds the loss in muscle mass (maximum force normalized to muscle cross-sectional area). The preferential loss of the molecular motor protein myosin, representing the hallmark of CIM, exhibiting a significant negative impact on the specific force generation by the muscle. Interestingly however, the preferential myosin loss is a relatively late event, and a specific loss in force generation capacity, is observed prior to the myosin loss. In the current study, employing an optimized cadmium telluride quantum dots (QD) mediated-thermometry approach to assess the efficiency of the myosin, we were able to determine the loss in specific force generated by the muscle, prior to the preferential loss of myosin. Reduction in QD fluorescent intensity correlates with greater heat loss, reflecting inefficient myosin function (less mechanical work performed and more heat loss on ATP hydrolysis by myosin). A significant decrease in myosin efficiency was observed in rats subjected to the ICU condition (immobilization and mechanical ventilation) for 5 days using an established experimental ICU model not limited by early mortality. Thus, qualitative myosin changes preceding quantitative myosin loss offer a mechanism underlying the early loss in specific force generation capacity associated with CIM and opens a venue for future CIM intervention strategies.

Abstract Migrants may be susceptible to vaccine barriers and hesitancy. We evaluated the association between migrant status, as measured by the citizenship from a High Migratory Pressure Country (HMPC), and COVID-19 vaccination uptake in the resident population in Rome, Italy. We also investigated sex differences. We followed participants for vaccination against COVID-19 in 2021. We calculated crude- and adjusted-vaccination rates and Cox hazard ratios of vaccination for migrants compared to Italians. Among migrants from HMPCs, we estimated HRs for females compared to males, stratifying by geographical area of origin. Models were adjusted for age and deprivation index and stratified by infection history. In 2021, among 1,731,832 18–64-year-olds, migrants were 55% less likely to uptake at least one COVID-19 vaccine dose than their Italian counterpart. Past SARS-CoV-2 infection reduced the difference between migrants and Italians to 27%. Among migrants from HMPCs, we observed a slight excess of vaccination uptake among females compared to males. Focusing on geographical areas, we observed that only females from central-western Asia were 9% less likely to uptake vaccination than males. Health communication strategies oriented to migrants and considering their different languages, cultures, and health literacy should be adopted for prevention before emergencies.

Abstract Background There is increasing evidence of crosstalk between organs. The neuromuscular junction (NMJ) is a peripheral chemical synapse whose function and morphology are sensitive to acetylcholine (ACh) release and muscle depolarization. In an attempt to improve our understanding of NMJ plasticity and muscle crosstalk, the effects of unilateral direct electrical stimulation of a hindlimb muscle on the NMJ were investigated in rats exposed long‐term post‐synaptic neuromuscular blockade. Methods Sprague Dawley rats were subjected to post‐synaptic blockade of neuromuscular transmission by systemic administration of α‐cobrotoxin and mechanically ventilated for up to 8 days and compared with untreated sham operated controls and animals exposed to unilateral chronic electrical stimulation 12 h/day for 5 or 8 days. Results NMJs produced axonal and glial sprouts (growth of processes that extend beyond the confines of the synapse defined by high‐density aggregates of acetylcholine receptors [AChRs]) in response to post‐synaptic neuromuscular blockade, but less than reported after peripheral denervation or pre‐synaptic blockade. Direct electrical soleus muscle stimulation reduced the terminal Schwann cell (tSC) and axonal sprouting in both stimulated and non‐stimulated contralateral soleus. Eight days chronic stimulation reduced (P

Abstract Background Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID‐19 pandemic, but underlying mechanisms remain elusive. Methods Ten neuro‐ICU patients exposed to long‐term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. Results (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro‐ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P 2) and activation of protein degradation pathways (false discovery rate [FDR] 65% during the 12 day observation period (muscle fibre cross‐sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P

Abstract Background Critical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a by‐product of critical care, attributed to impaired recovery, long‐term complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood; however, loss of mechanical stimuli contributes to critical illness‐associated muscle atrophy and weakness. Passive mechanical loading and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care. Methods Rats were subjected to 8 days of critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM. Results Following 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, myosin : actin ratio, and single muscle fibre maximum force normalized to cross‐sectional area (CSA; specific force) were reduced by 40–50% (P

Ventilator-induced diaphragm dysfunction (VIDD) is a common sequela of intensive care unit (ICU) treatment requiring mechanical ventilation (MV) and neuromuscular blockade (NMBA). It is characterised by diaphragm weakness, prolonged respirator weaning and adverse outcomes. Dissociative glucocorticoids (e.g., vamorolone, VBP-15) and chaperone co-inducers (e.g., BGP-15) previously showed positive effects in an ICU-rat model. In limb muscle critical illness myopathy, preferential myosin loss prevails, while myofibrillar protein post-translational modifications are more dominant in VIDD. It is not known whether the marked decline in specific force (force normalised to cross-sectional area) is a pure consequence of altered contractility signaling or whether diaphragm weakness also has a structural correlate through sterical remodeling of myofibrillar cytoarchitecture, how quickly it develops, and to which extent VBP-15 or BGP-15 may specifically recover myofibrillar geometry. To address these questions, we performed label-free multiphoton Second Harmonic Generation (SHG) imaging followed by quantitative morphometry in single diaphragm muscle fibres from healthy rats subjected to five or 10 days of MV + NMBA to simulate ICU treatment without underlying confounding pathology (like sepsis). Rats received daily treatment of either Prednisolone, VBP-15, BGP-15 or none. Myosin-II SHG signal intensities, fibre diameters (FD) as well as the parameters of myofibrillar angular parallelism (cosine angle sum, CAS) and in-register of adjacent myofibrils (Vernier density, VD) were computed from SHG images. ICU treatment caused a decline in FD at day 10 as well as a significant decline in CAS and VD from day 5. Vamorolone effectively recovered FD at day 10, while BGP-15 was more effective at day 5. BGP-15 was more effective than VBP-15 in recovering CAS at day 10 although not to control levels. In-register VD levels were restored at day 10 by both compounds. Our study is the first to provide quantitative insights into VIDD-related myofibrillar remodeling unravelled by SHG imaging, suggesting that both VBP-15 and BGP-15 can effectively ameliorate the structure-related dysfunction in VIDD.

Critical illness myopathy (CIM) detrimentally affects muscle function in ICU patients, with a dramatic loss of muscle mass and function where the loss in specific force exceeds the loss in muscle mass (maximum force normalized to muscle cross-sectional area). The preferential loss of the molecular motor protein myosin, representing the hallmark of CIM, exhibiting a significant negative impact on the specific force generation by the muscle. Interestingly however, the preferential myosin loss is a relatively late event, and a specific loss in force generation capacity, is observed prior to the myosin loss. In the current study, employing an optimized cadmium telluride quantum dots (QD) mediated-thermometry approach to assess the efficiency of the myosin, we were able to determine the loss in specific force generated by the muscle, prior to the preferential loss of myosin. Reduction in QD fluorescent intensity correlates with greater heat loss, reflecting inefficient myosin function (less mechanical work performed and more heat loss on ATP hydrolysis by myosin). A significant decrease in myosin efficiency was observed in rats subjected to the ICU condition (immobilization and mechanical ventilation) for 5 days using an established experimental ICU model not limited by early mortality. Thus, qualitative myosin changes preceding quantitative myosin loss offer a mechanism underlying the early loss in specific force generation capacity associated with CIM and opens a venue for future CIM intervention strategies. [ABSTRACT FROM AUTHOR]

The impact of the aerosol optical properties on the ultraviolet index (UVI) in the urban area of Rome is investigated in this study. In particular, the influence of aerosol optical depth (AOD) and single scattering albedo (SSA), estimated at the wavelength of 340 nm, and of the Ångström exponent, calculated in the range 340–500 nm, over a period of 11 years (2010–2020) in the months from March to September are analyzed. The UVI is monitored by a Brewer spectrophotometer, whereas measurements of the direct Sun and diffuse sky irradiances are performed by a co-located PREDE-POM sun–sky radiometer of the ESR/SKYNET network; the aerosol optical properties are obtained by the Skyrad MRIv2 retrieval. A novel method, based on physical principles and easily adaptable to other contexts, is developed to extrapolate the aerosol properties to the UV range during periods when only visible to near-infrared measurements are available. The retrievals from the sun–sky radiometer are consistent with the chemical characterization of urban PM10 (particulate matter 10 mm or less in diameter) samples collected during an intensive field campaign held in summer 2011 at the same site (URBan Sustainability Related to Observed and Monitored Aerosol – URBS ROMA). The PM macro components identified during the campaign are grouped in order to evaluate the contribution of the main macro sources (soil, sea, secondary inorganic, organics, and traffic) whose relative role is indeed expected to strongly affect the aerosol absorption capability. The surface forcing efficiency, calculated as the change in the UV index for a unit AOD variation, shows that AOD is the primary parameter affecting the surface irradiance under clear-sky conditions in Rome. SSA and the Ångström exponent are also identified as secondary influencing factors, i.e., the surface forcing efficiency is found to be greater for smaller zenith angles and for larger and more absorbent particles in the UV range (such as, e.g., mineral dust).

Abstract Background In Europe, one of the most consistent findings is that of migrant mortality advantage in high-income countries. Furthermore, the literature shows that economic shocks, which bring worse health outcomes, can severely affect the most disadvantaged individuals. We analyse differences and changes in all-cause mortality between Italians and migrants residing in Rome before, during, and in the aftermath of the Great Recession (2001–2015) by birth-cohort. Methods The analysis is a longitudinal open cohort study. Mortality data come from the Register of the Causes of Death (58,637 deaths) and the population denominator (n = 2,454,410) comes from the Municipal Register of Rome. By comparing three time-periods (2001–2005, 2006–2010, and 2011–2015), we analyse all-cause mortality of Rome residents born, respectively, in the intervals 1937–1976, 1942–1981, 1947–1986 (aged 25–64 years at entry into observation). Computing birth-cohort-specific death rates and applying parametric survival models with age as the time-scale, we compare mortality differences between migrants and Italians by gender, area of origin, and time-period. Results Overall, we find a lower risk of dying for migrants than Italians regardless of gender (Women: HR = 0.61, 95% CI 0.56–0.66; Men: HR = 0.49, 95% CI 0.45–0.53), and a lower death risk over time for the total population. Nevertheless, such a pattern changes according to gender and migrants’ area of origin. Conclusion Given the relevance of international migrations in Europe, studying migrants’ health has proved increasingly important. The deterioration in migrant health and the gradual weakening of migrants’ mortality advantage is likely to become a public health issue with important consequences for the healthcare system of all European countries.

Abstract Background Old age is associated with a significantly increased mortality in COVID-19 patients exposed to long-term controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection. However, our understanding of age-related differences in the response to CMV in the absence of a viral infection remains insufficient. Methods Young (7–8 months) and old (28–32 months) F344 BN hybrid rats were exposed to the ICU condition for 5 days, i.e., complete immobilization, mechanical ventilation, and extensive monitoring. Transcriptomic (RNA-Seq) and proteomics (Proximity Extension Assay) analyses of the diaphragm and proteomics analysis of plasma were conducted to investigate the molecular differences between young and old rats exposed to the ICU condition. Results According to multi-omics analyses, significant differences were observed in the diaphragm between young and old rats in response to 5 days CMV and immobilization. In young rats, metabolic pathways were primarily downregulated in response to immobilization (post-synaptic blockade of neuromuscular transmission). In old rats, on the other hand, dramatic immune and inflammatory responses were observed, i.e., an upregulation of specific related pathways such as “IL-17 signaling pathway”, along with a higher level of inflammatory factors and cytokine/chemokine in plasma. Conclusions The dramatically increased mortality in old ICU patients with COVID-19-associated hyperinflammation and cytokine storm need not only reflect the viral infection but may also be associated with the ventilator induced diaphragm dysfunction (VIDD) and hyperinflammatory responses induced by long-term CMV per se. Although mechanical ventilation is a life-saving intervention in COVID-19 ICU patients, CMV should be cautiously used especially in old age and other means of respiratory support may be considered, such as negative pressure ventilation.

Abstract Background Nanotoxicology is an increasingly relevant field and sound paradigms on how inhaled nanoparticles (NPs) interact with organs at the cellular level, causing harmful conditions, have yet to be established. This is particularly true in the case of the cardiovascular system, where experimental and clinical evidence shows morphological and functional damage associated with NP exposure. Giving the increasing interest on cobalt oxide (Co3O4) NPs applications in industrial and bio-medical fields, a detailed knowledge of the involved toxicological effects is required, in view of assessing health risk for subjects/workers daily exposed to nanomaterials. Specifically, it is of interest to evaluate whether NPs enter cardiac cells and interact with cell function. We addressed this issue by investigating the effect of acute exposure to Co3O4-NPs on excitation-contraction coupling in freshly isolated rat ventricular myocytes. Results Patch clamp analysis showed instability of resting membrane potential, decrease in membrane electrical capacitance, and dose-dependent decrease in action potential duration in cardiomyocytes acutely exposed to Co3O4-NPs. Motion detection and intracellular calcium fluorescence highlighted a parallel impairment of cell contractility in comparison with controls. Specifically, NP-treated cardiomyocytes exhibited a dose-dependent decrease in the fraction of shortening and in the maximal rate of shortening and re-lengthening, as well as a less efficient cytosolic calcium clearing and an increased tendency to develop spontaneous twitches. In addition, treatment with Co3O4-NPs strongly increased ROS accumulation and induced nuclear DNA damage in a dose dependent manner. Finally, transmission electron microscopy analysis demonstrated that acute exposure did lead to cellular internalization of NPs. Conclusions Taken together, our observations indicate that Co3O4-NPs alter cardiomyocyte electromechanical efficiency and intracellular calcium handling, and induce ROS production resulting in oxidative stress that can be related to DNA damage and adverse effects on cardiomyocyte functionality.

Abstract Background Global migration toward Europe is increasing. Providing health assistance to migrants is challenging because numerous barriers limit their accessibility to health services. Migrants may be at a greater risk of developing asthma and receiving lower quality healthcare assistance than non-migrants. We aim to investigate whether immigrants as children and adolescents have higher rates of potentially avoidable hospitalization (PAH) for asthma compared to Italians. Methods We performed a retrospective longitudinal study using six cohorts of 2–17-year-old residents in North and Central Italy from 01/01/2001 to 31/12/2014 (N = 1,256,826). We linked asthma hospital discharges to individuals using anonymized keys. We estimated cohort-specific age and calendar-year-adjusted asthma PAH rate ratios (HRRs) and 95% confidence intervals (95%CIs) among immigrants compared to Italians. We applied a two-stage random effect model to estimate asthma PAH meta-analytic rate ratios (MHRRs). We analyzed data by gender and geographical area of origin countries. Results Three thousand three hundred four and 471 discharges for asthma PAH occurred among Italians and immigrants, respectively. Compared to Italians, the asthma PAH cohort-specific rate was higher for immigrant males in Bologna (HRR:2.42; 95%CI:1.53–3.81) and Roma (1.22; 1.02–1.45), and for females in Torino (1.56; 1.10–2.20) and Roma (1.82; 1.50–2.20). Asthma PAH MHRRs were higher only among immigrant females (MHRRs:1.48; 95%CI:1.18–1.87). MHRRs by area of origin were 63 to 113% higher among immigrants, except for Central-Eastern Europeans (0.80; 0.65–0.98). Conclusion The asthma PAH meta-analytic rate was higher among female children and adolescent immigrants compared to Italians, with heterogeneity among cohorts showing higher cohort-specific PAH also among males, with some differences by origin country. Access to primary care for children and adolescent immigrants should be improved and immigrants should be considered at risk of severe asthma outcomes and consequently targeted by clinicians.

Abstract Background The Emergency Department (ED) can be considered an indicator of accessibility and quality and can be influenced in period of economic downturns. In the last fifteen years, the number of migrants in Italy has doubled (from 2.4 million in 2005 to 5.2 in 2019, 4.1 and 8.7% of the total population, respectively). However, evidence about migrants’ healthcare use is poor, and no studies focused on the ED utilisation rate during the Great Recession are available. This study aims to analyse trends in all-cause and cause-specific ED utilisation among migrants and Italians residing in Rome, Italy, before and after 2008. Methods Longitudinal study based on data from the Municipal Register of Rome linked to the Emergency Department Register from 2005 to 2015. We analysed 2,184,467 individuals, aged 25–64 in each year. We applied a Hurdle model to estimate the propensity to use the ED and to model how often individuals accessed the ED. Results Migrants were less likely to be ED users than Italians, except for Africans (RR = 1.46, 95%CI 1.40–1.52) and Latin Americans (RR = 1.04, 95%CI 1.00–1.08) who had higher all-cause utilisation rates than non-migrants. Compared to the pre-2008 period, in the post-2008 we found an increase in the likelihood of being an ED user (OR = 1.34, 95%CI 1.34–1.35), and a decrease in ED utilisation rates (RR = 0.96, 95%CI 0.96–0.97) for the whole population, with differences among migrant subgroups, regardless of cause. Conclusions This study shows differences in the ED utilisation between migrants and Italians, and within the migrant population, during the Great Recession. The findings may reflect differentials in the health status, and barriers to access primary and secondary care among migrants. In this regard, health policies and cuts in health spending measures may have played a key role, and interventions to tackle health and access disparities should include policy measures addressing the underlying factors, adopting a Health in All Policies perspective. Further researches focusing on specific groups of migrants, and on the causes and diagnoses related to the ED utilisation, may help to explain the differences observed.

Titin is considered an integrator of muscle cell proteins but direct evidence is limited. Here, titin is inactivated in adult mouse muscles, which causes sarcomere disassembly, protein mis-expression and force impairment, recapitulating key alterations in critical illness myopathy patient muscles.