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Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (C max) and area under the plasma concentration–time curve between time zero and the last quantifiable timepoint (AUC 0–t) for the analytes were between 80 and 125 %. In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB C max in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for C max and 127.34 % for AUC 0–t). In Study 1, GB AUC 0–t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for C max and 129.12 % for AUC 0–t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC 0–t , although not for C max. Both formulations were similarly well tolerated in all three studies. Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/ FF /GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential. • Use of propellants with high global warming potential (such as HFA-134a) inpMDIs is being phased down. • The combination of BDP/FF/GB is now being reformulated using the low global warming potential propellant HFA-152a. • These three studies compared BDP/FF/GB pharmacokinetics when delivered via pMDI using HFA-152a vs HFA-134a as propellant. • Overall, these data suggest therapeutic equivalence of the new formulation and the existing BDP/FF/GB pMDI formulation. [ABSTRACT FROM AUTHOR]

Overt hepatic encephalopathy (OHE) is a major complication of transjugular intrahepatic portosystemic shunt (TIPS) placement, given its high incidence and possibility of refractoriness to medical treatment. Nevertheless, the impact of post-TIPS OHE on mortality has not been investigated in a large population. We designed a multicenter, non-inferiority, observational study to evaluate the mortality rate at 30 months in patients with and without OHE after TIPS. We analyzed a database of 614 patients who underwent TIPS in three Italian centers and estimated the cumulative incidence of OHE and mortality with competitive risk analyses, setting the non-inferiority limit at 0.12. During a median follow-up of 30 months (IQR 12-30), 293 patients developed at least one episode of OHE. Twenty-seven (9.2%) of them experienced recurrent/persistent OHE. Patients with OHE were older (64 [57-71] vs. 59 [50-67] years, p < 0.001), had lower albumin (3.1 [2.8-3.5] vs. 3.25 [2.9-3.6] g/dl, p = 0.023), and had a higher prevalence of pre-TIPS OHE (15.4% vs. 9.0%, p = 0.023). Child-Pugh and MELD scores were similar. The 30-month difference in mortality between patients with and without post-TIPS OHE was 0.03 (95% CI -0.042 to 0.102). Multivariable analysis showed that age (subdistribution hazard ratio 1.04, 95% CI 1.02–1.05, p < 0.001) and MELD score (subdistribution hazard ratio 1.09, 95% CI 1.05–1.13, p < 0.001), but not post-TIPS OHE, were associated with a higher mortality rate. Similar results were obtained when patients undergoing TIPS for variceal re-bleeding prophylaxis (n = 356) or refractory ascites (n = 258) were analyzed separately. The proportion of patients with persistent OHE after TIPS was significantly higher in the group of patients who died. The robustness of these results was increased following propensity score matching. Episodic OHE after TIPS is not associated with mortality in patients undergoing TIPS, regardless of the indication. Overt hepatic encephalopathy (OHE) is a common complication in patients with advanced liver disease and it is particularly frequent following transjugular intrahepatic portosystemic shunt (TIPS) placement. In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival, regardless of the severity of cirrhosis or the presence of acute-on-chronic liver failure. In this multicenter, non-inferiority, observational study we demonstrated that post-TIPS OHE does not increase the risk of mortality in patients undergoing TIPS, irrespective of the indication. This finding alleviates concerns regarding the weight of this complication after TIPS. Intensive research to improve patient selection and risk stratification remains crucial to enhance the quality of life of patients and caregivers and to avoid undermining the positive effects of TIPS on survival. [Display omitted] • In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival. • OHE is considered a major complication in patients treated with TIPS. • We show that post-TIPS episodic OHE does not increase the risk of death in patients undergoing TIPS, irrespective of the indication. • This finding alleviates concerns regarding the impact of this complication on survival after TIPS. [ABSTRACT FROM AUTHOR]

We report a case of Enterocytozoon bieneusi infection in a pediatric hematopoietic stem cell transplant recipient in Argentina. Spores were visualized in feces using Calcofluor White and modified trichrome stainings. PCR and sequencing identified E. bieneusi genotype D in fecal samples and liver samples, confirming extraintestinal dissemination of the parasite.

We report a case of Enterocytozoon bieneusi infection in a pediatric hematopoietic stem cell transplant recipient in Argentina. Spores were visualized in feces using Calcofluor White and modified trichrome stainings. PCR and sequencing identified E. bieneusi genotype D in fecal samples and liver samples, confirming extraintestinal dissemination of the parasite. [ABSTRACT FROM AUTHOR]

Narrative Medicine and Nursing are clinical-supporting intervention methodologies that aim to enhance professionals’ communication skills and place patients at the heart of their therapeutic path. A narrative interview (NI) is a communication tool between practitioner and patient. The role of NI is debated extensively in the literature, but no studies focus on its use by nurses responsible for first-diagnosed cancer patients.This study aimed to evaluate the feasibility and utility of NI, carried out by Nurses, in managing people recently diagnosed with cancer.A pilot mixed-methods study with before-and-after-intervention evaluation, qualitative longitudinal data analysis, and concurrent data triangulation was conducted. The Mini-Mental Adjustment to Cancer assessed disease adaptation, while the Psychological Distress Inventory investigated psychological distress. The qualitative analysis of the narrative interviews assessed the usefulness of this intervention.13 out of 14 eligible patients took voluntary part in the study. Of those, 9 (69 %) completed T1 and T2 questionnaires and NI. The following five themes emerged from thematic analysis: reaction to the disease, feelings related to the new condition of life, changes, importance of relationships and perception of care. Patients reported being highly stressed and recognized the importance of a supporting social network for better coping with the condition.The adoption of an NI approach at the time of cancer diagnosis is feasible. Due to the limited sample size, it is unclear if NI may positively impact psychological distress in this patient population. Further studies would benefit from the integration of an additional investigation tool aiming to clarify whether NI promotes disease awareness in cancer patients. Furthermore, the recruitment of a larger sample is equally recommended.

Background: The COVID-19 pandemic appeared as an unpredictable disruption of daily activities. This situation produced a unique mental health impact for the general population, youth, and vulnerable groups. A documented consequence has been alcohol abuse and impaired mental health. To our knowledge, no published study has yet evaluated the rates of depressive symptoms, academic frustration, and substance abuse in the Italian student population in the COVID era linking them to sociodemographic variables. Aims: To investigate the incidence of depressive symptoms, academic frustration, and substance abuse students developed in one university in Northern Italy during the first COVID-19 outbreak, using a student wellbeing framework borrowed from Allardt's and Bronfenbrenner's theories. Methods: Descriptive statistics, correlations, Wilcoxon test and factorial ANOVA were performed on data gathered through an online questionnaire sent to a convenience sample of university students. Data collection occurred between 18 May and June 21, 2020. Results: According to the framework used, Being was the dimension of sociodemographic variables, Having was economic support and Loving was social support. Students experienced academic frustration and related depressive symptoms. Male gender seemed to be less affected by the depressive syndrome. With regard to economic support and related repercussions on depressive symptoms, students who reported that they could not obtain a loan showed significantly higher depressive symptoms. Students benefiting from greater financial support showed less academic frustration. Age appeared to be a predictor of academic frustration since young students proved to be the most frustrated. The examined students’ population showed a significant decrease in alcohol and cigarettes consumption. Conclusions: Having and Being dimensions influenced depression and academic frustration. Having and Loving dimensions were related with use of substances. The study findings support the implementation of interventions to help students, at a psychological, social, financial level aiming at fostering the quality of students’ educational life.

ABSTRACTFasciolosis is a parasitic disease considered as emerging and neglected by the WHO. Sheep are highly susceptible to this disease, and affected flocks experience decreased productivity due to increased mortality, and the reduced quality of their products, such as wool and meat. To effectively control this disease, reliable and early diagnosis is essential for making decisions regarding antiparasitic application and/or the removal of affected animals. Currently, the diagnosis of F. hepatica in sheep relies on the detection of parasite eggs in faeces, a method that becomes reliable from week 10 post-infection. Consequently, there is a need for earlier diagnostic tools based on immune response. However, obtaining antigens for antibody detection has proven to be difficult and expensive. The aim of this study was to evaluate members of the Kunitz protein family of F. hepatica expressed in the form of a fusion protein in the serological diagnosis of F. hepatica in sheep. The performance of three recombinant F. hepatica Kunitz-type inhibitors (FhKT1.1, FhKT1.3, and FhKT4) was compared with a synthetic Kunitz-type peptide (sFhKT) in sera from sheep experimentally infected with F. hepatica, using an ELISA. Of these, FhKT1.1 showed the most promising diagnostic indicators, exhibiting high precision and low cross-reactivity, and thus potential for standardized production. The results of our study demonstrated that the application of FhKT1.1 is a valuable tool for early-stage diagnosis of F. hepatica in sheep. Such an early diagnosis can aid in implementing timely interventions and effectively managing the disease in sheep populations.

Abstract Background This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. Methods Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. Results There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (− 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: − 51.1% and − 57.2%, V2 and V3, respectively; all p

Introduction: Nurses are at high risk of developing a psychiatric disorder as a result of exposure to stressful and/or traumatic events experienced in the workplace. Specifically, they may develop long-term depression or post-traumatic stress disorder (PTSD). The spread of the COVID-19 pandemic has exposed nurses to stressful working conditions. The aim of this study was to investigate the effects of mental and physical stress on nurses who provided assistance in the Emergency Room (ER) of Piacenza Hospital during the COVID-19 pandemic. Methods: A sample of 43 nurses working in the ER from 8 March to 3 May 2020 was enrolled. Each nurse was asked to fill in a form containing socio-demographic data and the "Screening Questionnaire for Disaster Mental Health" (SQD). The study was approved by the Ethics Committee of the Area Vasta Emilia Nord. Results: The SQD-D sub-scale results showed that 38 out of 43 nurses (88%) had “less likely to be depressed” and the remaining 5 (12%) had “more likely to be depressed”. Regarding the likelihood of developing PTSD, SQD-P sub-scale results, 29 nurses (67%) little possibility to be affected, 8 nurses (19%) classify themselves as moderately affected, and finally 6 nurses present as severely affected. The Cronbach's alpha for the scale was 0.80, for the SQD-P was 0.73 and for the SQD-D it was 0.68. The correlations between age and SQD and between years of service and SQD were not statistically significant. Conclusions: The study showed that some nurses are at high risk of developing depression or PTSD in stressful work situations such as those caused by COVID-19. These data can be used to suggest preventive measures such as psychological support.

Bowel dysfunction is a common consequence of neurological diseases and has a major impact on the dignity and quality of life of patients. Evidence on neurogenic bowel is focused on spinal cord injury and multiple sclerosis; few studies have focused on patients with acquired brain injury (ABI). Neurogenic bowel dysfunction is related to a lifelong condition derived from central neurological disease, which further increases disability and social deprivation. The manifestations of neurogenic bowel dysfunction include fecal incontinence and constipation. Almost two out of three patients with central nervous system disorder have bowel impairment. This scoping review aims to comprehend the extent and type of evidence on bowel dysfunction after ABI and present conservative treatment. For this scoping review, the PCC (population, concept, and context) framework was used: patients with ABI and bowel dysfunction; evaluation and treatment; and intensive/extensive rehabilitation path. Ten full-text articles were included in the review. Oral laxatives are the most common treatment. The Functional Independence Measure (FIM) subscale is the most common scale used to assess neurogenic bowel disease (60%), followed by the Rome II and III criteria, and the colon transit time is used to test for constipation; however, no instrumental methods have been used for incontinence. An overlapping between incontinence and constipation, SCI and ABI increase difficulties to manage NBD. The need for a consensus between the rehabilitative and gastroenterological societies on the diagnosis and medical care of NBD.Systematic review registrationOpen Science Framework on August 16, 2022 https://doi.org/10.17605/OSF.IO/NEQMA.

Abstract One of the main reasons why insect pollinators are declining is a lack of floral resources. In agricultural landscapes, remaining seminatural grasslands play a key role for providing such resources. However, droughts pose an increasing threat to the abundance and continuity of flowers. Soil amendments are a novel management tool for Swedish grasslands aiming to increase carbon sequestration and soil water holding capacity. In this study, we examined how drought is affecting floral resources (i.e. floral units, nectar quantity and nectar continuity) in grasslands with different mowing regimes, and if soil amendments could mitigate potential negative drought effects. In summer 2019, we set up an experiment combining rain‐out shelters (‘drought’), soil amendments (‘compost’) and different mowing regimes (‘mown’ vs. ‘abandoned’) in four extensively managed Swedish grasslands (48 plots, size 2 m2). Between May and August 2021, we counted the floral units nine times in each plot. We derived values for the nectar sugar production per floral unit from an existing database. We observed a decrease in floral units under drought in the mown, but not in the abandoned plots. Nectar quantity and continuity over the season were not significantly affected by drought across both mowing regimes—in the abandoned plots the nectar provision even extended slightly in duration (towards late summer). The compost treatment had positive effects on the floral units, nectar quantity and continuity (extending it towards early summer) in the mown, but not in the abandoned plots. The plant species in our study reacted differently to the treatments. Most of the nectar was provided by only few species (mainly Lathyrus pratensis, Vicia cracca and Anthriscus sylvestris). The results are species specific, thus other plant communities might respond differently. However, our experiment shows that nectar provision (based on database values) in grasslands with a native plant community and natural soil conditions remains relatively stable under drought. We also found that soil amendments increase floral resources in managed grasslands.

In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e. , HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension. [Display omitted] • Models that can non-invasively assess portal hypertension severity are an unmet clinical need. • Machine learning models trained on 3/5 laboratory parameters enabled non-invasive assessment of portal hypertension severity. • These models could predict portal pressures of ≥10 mmHg or ≥16 mmHg in individuals with compensated cirrhosis. • An online tool based on these models has been made available and can be used for portal hypertension risk stratification. [ABSTRACT FROM AUTHOR]

Vitamin D is a crucial nutrient with many pleiotropic effects on health and various chronic diseases. The purpose of this review is to provide a detailed report on the pathophysiological mechanisms underlying vitamin D deficiency in patients with chronic liver disease, addressing the different liver etiologies and the condition of advanced chronic liver disease (cirrhosis) with related complications. To date, patients with liver disease, regardless of underlying etiology, have been shown to have reduced levels of vitamin D. There is also evidence of the predictive role of vitamin D values in complications and progression of advanced disease. However, specific indications of vitamin D supplementation are not conclusive concerning what is already recommended in the general population. Future studies should make an effort to unify and validate the role of vitamin D supplementation in chronic liver disease. [ABSTRACT FROM AUTHOR]

Abstract Background A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. Methods TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1)

• Mannitol is a hyperosmotic agent administered BID via dry-powder inhaler for CF. • This study provides confirmatory evidence on the use of mannitol in adults with CF. • Mannitol 400 mg BID provided significant improvements in FEV 1 versus control. • These improvements were supported by secondary pulmonary function endpoints. • Mannitol 400 mg BID was well tolerated, with few treatment-related adverse events. : Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults. : This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV 1) 40–90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV 1 averaged over the 26-week treatment period. : Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV 1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV 1 averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively. : In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV 1) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353. [ABSTRACT FROM AUTHOR]

Background: A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan.Methods: TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint.Results: Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup.Conclusions: In patients with COPD, FEV1 < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ). [ABSTRACT FROM AUTHOR]

Dermatophytoses (ringworms) are among the most frequent skin infections and are a highly prevalent cause of human disease worldwide. Despite the incidence of these superficial mycoses in healthy people and the compelling evidence on chronic and deep infections in immunocompromised individuals, the mechanisms controlling dermatophyte invasion in the skin are scarcely known. In the last years, the association between certain primary immunodeficiencies and the susceptibility to severe dermatophytosis as well as the evidence provided by novel experimental models mimicking human disease have significantly contributed to deciphering the basic immunological mechanisms against dermatophytes. In this review, we outline the current knowledge on fungal virulence factors involved in the pathogenesis of dermatophytoses and recent evidence from human infections and experimental models that shed light on the cells and molecules involved in the antifungal cutaneous immune response. The latest highlights emphasize the contribution of C-type lectin receptors signaling and the cellular immune response mediated by IL-17 and IFN-γ in the anti-dermatophytic defense and skin inflammation control.

The aim of this article is to investigate on the European efforts to keep détente alive during the 1980’s, focusing in particular on the relations with the Soviet Union. The European policy will be analysed from the peculiar perspective of the European Political Cooperation (EPC), the mechanism of coordination of the European Community (EC) member states foreign policies, which anticipated the Common Foreign and Security Policy (CFSR) established by the Maastricht Treaty of 1992. The article is divided in two parts: after a short description of the EPC’s functioning and of its main achievements during the 1970’s, the first part addresses the European interest in revitalizing détente in the first half of the 1980’s, focusing in particular on the Polish case in 1981. The second part deals with the issue of the relationship between the EC and Soviet Union after the Single European Act (SEA) signature in 1986. Although the Single European Act was not originally designed to deal with foreign policy issues, as its main goal was to complete the Single market, it represented a significant stage also for the development of a European foreign policy. For the first time it included the scope of a common foreign policy, linking the EC procedures, in a single legal instrument to the EPC. The article will deal with the issue of “consistency”, or, in other words, the increasing recourse made by EPC to EC instruments (and vice-versa) as sanctions or the use of conditionality in economic assistance, in order to further EC’s policies. In particular the article will investigate if the completion of the Single market and the revival of European integration in the second half of the 1980’s affected USSR policy, wondering in particular if it influenced the development of Gorbachev’s project of a European common home. L’articolo descrive gli sforzi delle nazioni europee di mantenere in vita il processo di distensione tra i due blocchi durante la prima metà degli anni Ottanta, analizzando in particolare le relazioni tra la Cee e l’Unione Sovietica. La politica europea verrà ricostruita attraverso la prospettiva della Cooperazione Politica Europea (CPE), il meccanismo di coordinamento delle politiche estere dei paesi membri della CEE, che ha preceduto la PESC, creata con il Trattato di Maastricht del 1992. L’articolo è diviso in due parti: dopo una sintetica descrizione della CPE, del suo funzionamento e dei suoi principali successi nel corso degli anni Settanta, la prima parte ricostruisce le principali iniziative delle nazioni europee tese a rivitalizzare la distensione nella prima metà degli anni Ottanta, analizzando in particolare il caso della Polonia nel 1981. La seconda parte ricostruisce invece le relazioni tra la Cee e l’Unione Sovietica dopo la firma dell’Atto Unico Europeo nel 1986. Sebbene l’Atto Unico Europeo sia soprattutto ricordato per avere completato e dato vita al mercato unico, esso rappresentò un importante momento di svolta anche per lo sviluppo di una politica estera europea. Finalmente la CPE veniva inserita e diventava parte integrante dei Trattati. L’articolo si sofferma in particolare sull’importanza del principio di “coerenza” tra le dichiarazioni politiche adottate dai governi con la CPE e il crescente ricorso da parte della CEE a forme di assistenza economica condizionata o a sanzioni economiche. In particolare, l’articolo cercherà di comprendere se il completamento del mercato unico e il rilancio dell’integrazione europea nella seconda metà degli anni Ottanta influenzarono la politica estera dell’URSS e il progetto di Casa Comune europea di Gorbacëv. Parole chiave: Détente, Cooperazione politica europea, Mercato commune europeo, principio di coerenza, Mikhail Gorbacëv, Casa comune europea

Mechanisms of transcriptional repression are important during cell differentiation. Mammalian heterochromatin protein 1 isoforms HP1α, HP1β, and HP1γ play important roles in the regulation of chromatin structure and function. We explored the possibility of different roles for the three HP1 isoforms in an integrated system, skeletal muscle terminal differentiation. In this system, terminal differentiation is initiated by the transcription factor MyoD, whose target genes remain mainly silent until myoblasts are induced to differentiate. Here we show that HP1α and HP1β isoforms, but not HP1γ, interact with MyoD in myoblasts. This interaction is direct, as shown using recombinant proteins in vitro. A gene reporter assay revealed that HP1α and HP1β, but not HP1γ, inhibit MyoD transcriptional activity, suggesting a model in which MyoD could serve as a bridge between nucleosomes and chromatin-binding proteins such as HDACs and HP1. Chromatin immunoprecipitation assays show a preferential recruitment of HP1 proteins on MyoD target genes in proliferating myoblasts. Finally, modulation of HP1 protein level impairs MyoD target gene expression and muscle terminal differentiation. Together, our data show a nonconventional interaction between HP1 and a tissue-specific transcription factor, MyoD. In addition, they strongly suggest that HP1 isoforms play important roles during muscle terminal differentiation in an isoform-dependent manner. [ABSTRACT FROM AUTHOR]

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) were reported less frequently during the COVID-19 pandemic. We report real-world data on COPD exacerbation rates before and during this pandemic., Methods: Exacerbation patterns were analysed using electronic medical records or claims data of patients with COPD before (2017-2019) and during the COVID-19 pandemic (2020 through early 2022) in France, Germany, Italy, the United Kingdom and the United States. Data from each country were analysed separately. The proportions of patients with COPD receiving maintenance treatment were also estimated., Results: The proportion of patients with exacerbations fell 45-78% across five countries in 2020 versus 2019. Exacerbation rates in most countries were reduced by >50% in 2020 compared with 2019. The proportions of patients with an exacerbation increased in most countries in 2021. Across each country, seasonal exacerbation increases seen during autumn and winter in pre-pandemic years were absent during the first year of the pandemic. The percentage of patients filling COPD prescriptions across each country increased by 4.53-22.13% in 2019 to 9.94-34.17% in 2021., Conclusion: Early, steep declines in exacerbation rates occurred in 2020 versus 2019 across all five countries and were accompanied by a loss of the seasonal pattern of exacerbation., Competing Interests: F.J. Martinez reports support for the present manuscript from Chiesi Farmaceutici S.p.A.; reports grants or contracts from AstraZeneca, Chiesi Farmaceutici S.p.A., GSK and Sanofi/Regeneron; reports consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., CSL Behring, GSK, Novartis, Polarean, Pulmatrix, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris and UpToDate®; reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca and GSK; and reports participation on a Data Safety Monitoring Board or advisory board for GSK and Medtronic. A. Papi reports study support from Chiesi Farmaceutici S.p.A.; reports grants or contracts from Agenzia Italiana del Farmaco (AIFA), AstraZeneca, Chiesi Farmaceutici S.p.A., GSK and Sanofi; reports consulting fees from AstraZeneca, Avillion, Chiesi Farmaceutici S.p.A., Elpen Pharmaceuticals, GSK, Novartis, Roche and Sanofi; reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Avillion, Chiesi Farmaceutici S.p.A., Edmond Pharma, Elpen Pharmaceuticals, GSK, IQVIA, Menarini, Mundipharma, Novartis, Sanofi and Zambon; and reports advisory board membership for AstraZeneca, Avillion, Chiesi Farmaceutici S.p.A., Elpen Pharmaceuticals, GSK, IQVIA, MSD, Novartis, Regeneron and Sanofi. T. Welte reports all support for the present manuscript from Chiesi Farmaceutici S.p.A.; reports consulting fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A. and GSK; and reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A. and GSK. He also reports a grant paid to his institution from the German Ministry of Research and Education. D. Singh reports consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., Cipla, CSL Behring, EpiEndo, Genentech, GSK, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance Biopharma and Verona Pharma. D. Singh is also supported by the National Institute for Health Research Manchester Biomedical Research Centre. D.V. Galkin is an employee of Chiesi Farmaceutici S.p.A.; reports support for this manuscript from Chiesi Farmaceutici S.p.A.; and holds stock or stock options with GSK. A. Guasconi is an employee of Chiesi Farmaceutici S.p.A. S. Pirondi is an employee of Chiesi Farmaceutici S.p.A. and is on SiMEF Società Italiana di Medicina Farmaceutica Working Group on Observational Studies. G. Georges is an employee of Chiesi Farmaceutici S.p.A. J. Imperato and R. Hermans are employees of IQVIA and were on the consulting team that led the analysis of the real-world data for this manuscript. The authors report no other conflicts of interest in this work., (© 2024 Martinez et al.)

Background: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function., Methods: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siV aw ) and resistance (siR aw ) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siV aw and siR aw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siV aw and siR aw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV 1 ) and COPD Assessment Test (CAT) were also assessed., Results: There were no significant changes in pre-dose siV aw or siR aw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siR aw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siV aw and siR aw (siV aw : 39.8% and 62.6%; siR aw : - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siV aw : 77.9%; siR aw : - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV 1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001)., Conclusions: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Three 52-week studies in COPD have assessed the efficacy and safety of single-inhaler extrafine formulation triple therapy combining beclomethasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) delivered via pressurized metered-dose inhaler (pMDI). BDP/FF/G is now being developed for delivery via multi-dose dry-powder inhaler (DPI; NEXThaler). This study aimed to demonstrate non-inferiority of BDP/FF/G DPI vs pMDI for lung function., Methods: Multicenter, randomized, double-blind, double-dummy, active-controlled, three-way cross-over study in patients with COPD and post-bronchodilator forced expiratory volume in 1 second (FEV 1 ) 30-80% predicted. Patients received BDP/FF/G 100/6/10µg via DPI and pMDI, and BDP/FF 100/6µg via pMDI, all two inhalations twice daily for four weeks, with treatments separated by two-week washout. The two co-primary objectives were to demonstrate non-inferiority between the two BDP/FF/G formulations for FEV 1 area under the curve between 0 and 12 hours post-dose (AUC 0-12h ) normalized by time and trough FEV 1 at 24 hours, both on Day 28. EudraCT 2017-004405-41., Results: Of 449 patients screened, 366 were randomized, with 342 (93.4%) completing all three treatment periods. The primary objectives were met, with changes from baseline in FEV 1 AUC 0-12h and trough FEV 1 on Day 28 similar for the two BDP/FF/G formulations, and the confidence intervals for the difference lying entirely within the pre-specified non-inferiority criterion (-50mL): -20 (-35, -6) mL and 3 (-15, 20) mL for AUC 0-12h and trough FEV 1 , respectively. BDP/FF/G pMDI and DPI were statistically superior to BDP/FF for these endpoints (p<0.001). A similar proportion of patients experienced adverse events with each treatment (15.5%, 18.7% and 15.4% with BDP/FF/G DPI and pMDI, and BDP/FF, respectively); the majority were mild or moderate, with few related to treatment., Conclusion: Extrafine BDP/FF/G DPI and pMDI demonstrated similar efficacy and safety in patients with COPD, supporting the DPI formulation as a valid alternative., Competing Interests: KMB is a full time employee of insaf Respiratory Research Institute. He has received personal or institutional compensations for services on advisory boards or consulting for AstraZeneca, Berlin Chemie, Boehringer, Chiesi, Elpen, GSK, Mundipharma, Novartis, Pohl Boskamp, Sanofi, sterna and Zentiva, and compensations for speaker activities in scientific meetings supported by AstraZeneca, Berlin Chemie, Boehringer, ERT, GSK, Novartis, Pfizer, Pohl Boskamp, Sanofi and Teva, all outside the submitted work. The institution has received compensations for design and performance of clinical trials from AstraZeneca, Boehringer, Chiesi, GSK, Novartis, Parexel, Pearl Therapeutics, sterna, and Zentiva. PK reports personal fees from Chiesi, Novartis, AstraZeneca, Boehringer Ingelheim, Berlin Chemie Menarini, Adamed, Polpharma and Lekam, all outside the submitted work and reports lectures for Novartis, GSK, Teva, AstraZeneca, Polpharma, and Lekam, outside the submitted work. MC received grants and honoraria for lectures from Chiesi Farmaceutici SpA, outside the submitted work. IV, AG and GG are employees of Chiesi Farmaceutici SpA, the sponsor of the study. The authors report no other potential conflicts of interest for this work., (© 2021 Beeh et al.)