Chiesi (Italy)

ABSTRACT Background Most births worldwide (>80%) occur in health care facilities, yet 2.3 million newborns die annually. If the know – do gap between evidence and implementation was closed, an estimated 752,000 newborn deaths could be prevented per year. To bridge this gap, we describe the co-design of the Implementation Toolkit for Small and Sick Newborn Care (Newborn Toolkit), a web platform and linked community of global implementers, facilitated by NEST360 and UNICEF. The Newborn Toolkit enables access to practical, curated resources, including tools for peer learning and adaptation to country contexts. Methods A systematic three step process was followed. Step 1) Structure: We used an organising framework of WHO and UNICEF ten core components for health systems strengthening. We then reviewed relevant knowledge management platforms to identify elements facilitating user engagement. Step 2) Content: >300 implementers collated publications and tools for ten core components. Step 3) Refining and building community: User data analytics and surveys plus direct feedback from the global communities of practice provided data to improve website and webinar content. Results Step 1) Structure: In 2020, the Newborn Toolkit website structure was co-designed based on the ten core components. Step 2) Content: Working groups, organised by core components, collated over 1,100 resources in 15 languages. Step 3) Refining and building community: Cross-country learning was facilitated through 45 webinars with multi-disciplinary speakers from all continents including caregivers, clinicians, non-governmental organisation representatives, engineers, and data scientists. French language translation and engagement was added between 2023-2025. Unique user counts increased with 28,146 in 2023 to 62,561 in 2025 from 198 countries and territories. The most viewed content includes WHO guidelines, neonatal floor plans, the ABC device costing tool, and data tools. Conclusions Given the urgency for accelerated progress for newborn survival by 2030, rapid implementation of proven solutions is needed. It is crucial that implementers can access evidence and tools to adapt for their specific context, rather than “reinventing the wheel”. Systems change is complex, requiring novel approaches to make it doable, such as standard, simplified action pathways available on the Newborn Toolkit. Gaps to address include evidence availability in multiple languages. KEY FINDINGS WHAT WAS KNOWN? 2.3 million neonatal deaths are estimated annually and 65 countries are at-risk of missing Sustainable Development Goal 3.2 of reducing the number of neonatal deaths to less than 12 per 1,000 live births by 2030 There exists a know–do gap in global newborn health referring to the inability to translate evidence, what is known to work, into practice to improve health outcomes for WHO-UNICEF level-2 Small and Sick Newborn Care Frameworks based on country experiences have been created to guide health systems strengthening such as the WHO/UNICEF core components; however, operationalisation is needed Evidence, guidelines, and resources for Small and Sick Newborn Care were available; however, there existed a gap in knowledge management platforms dedicated to enabling evidence-based implementation of health systems strengthening interventions in low-resource settings WHAT WAS DONE THAT IS NEW? We co-designed a knowledge management platform for resources including tools, readings, and case studies to bridge the know–do gap for Small and Sick Newborn Care in low-resource settings Content and resources on the site were organised according to the ten WHO/UNICEF core components for health systems strengthening plus infection prevention and control This platform was operationalised and scaled by linking to, and engaging with, a global community of practice We applied a continuous learning and feedback integration approach to develop and refine content, enable accessibility including by language, and tailor engagement initiatives to implementer needs informed by website user and webinar data analytics WHAT WAS FOUND? The platform hosts over 1,100 tools and readings with resources available in 15 languages Between 2021–2025, this platform had 157,452 unique users, from 198 countries and territories 45 webinars were hosted between 2022–2025 showcasing implementation case studies and facilitating cross-country learning Knowledge management and targeted engagement can enable uptake of information by organising content in practical, digestible, and feasible formats WHAT NEXT? The know–do gap in Small and Sick Newborn Care needs to be closed. Providing up-to-date, relevant evidence that adapts to emerging knowledge and local learning, alongside leadership and financial inputs, could facilitate quality care delivery through data-driven decision making Bridging language barriers, through content translation, is a priority and crucial to enable wider access to up-to-date evidence

BackgroundWomen are at greater risk of developing sporadic Alzheimer's disease (AD). While their longer lifespans contribute to AD‐risk, this factor does not fully explain the observed sex differences. Increased glial activation and neuroinflammation associated with female‐sex may play a role. Glial fibrillary acidic protein (GFAP), a marker of astrocyte activation and neuroinflammation, has been linked to AD‐ risk. In preclinical and prodromal AD, higher brain GFAP levels are associated with cognitive decline, Aβ deposition, tau spread, and neurodegeneration associated with AD. Studies have reported that plasma GFAP levels are higher in women compared to men, but few have thoroughly examined this influence. This prompted us to examine sex‐differences in plasma GFAP in cognitively unimpaired older adults and its relationship to cognitive performance and other plasma AD biomarkers, both at baseline and longitudinally.MethodParticipants were enrolled in the Memory Education and Research Initiative (MERI) program and completed a neuropsychological battery, clinical and psychiatric evaluation, and blood draw. Plasma GFAP, Aβ42, Aβ40 concentrations were measured using single‐molecule array (SIMOA) platform. Participants were included if they gave blood (2+ timepoints), MMSE>23 at Baseline, and age 50‐85. Analysis of covariance (ANCOVA) was conducted to assess for sex differences, and longitudinal analyses using linear mixed models were conducted to examine associations with cognition.ResultA total 325 MERI (mean age=72 years; 59% females) were included in the analysis. ANCOVA, controlling for age, showed significantly higher plasma GFAP levels in females compared to males (p = 0.001). Longitudinal analysis of 229 MERI revealed that higher baseline GFAP is associated with lower MMSE scores over time (Figure 1, p = 0.002). When stratified by sex, these associations remained significant in females but not males (p = 0.002). GFAP was also inversely associated with Aβ42/40 over time (Figure 2, p <0.001) in females.ConclusionCognitively unimpaired females had higher levels of plasma GFAP compared to males. Moreover, elevated GFAP levels associated with greater decline in global cognition and lower Aβ42/40 in females but not males. These findings suggest increased astrocytic activation that may lead to cognitive decline in females. More studies are needed to understand how sex‐differences in neuroinflammation may impact future AD‐risk. Potential mechanisms will be discussed.

Background: Tanimilast is a novel phosphodiesterase-4 inhibitor under clinical development for the maintenance therapy of asthma and chronic obstructive pulmonary disease (COPD). Since tanimilast is inhaled, it is important to evaluate lung deposition as part of its clinical development. The current study, therefore, used functional respiratory imaging, a validated, noninvasive quantification imaging methodology, to evaluate the lung deposition of tanimilast in patients with asthma or COPD. Methods: This retrospective study used data from 12 patients with asthma and 12 patients with COPD, primarily selected based on disease severity. Patients with COPD had chronic bronchitis,withminimal high-resolution computerized tomography evidence of emphysema. Total intrathoracic, central, distal, peripheral, and extrathoracic deposition of tanimilast 400 µg and 800 µg was evaluated using three inhalation profiles-inhalation durations of 1, 2, and 3 seconds, with associated peak flows of 100, 60, and 45 L/min, respectively. Results: Intrathoracic deposition as a percentage of the delivered dose was similar in asthma and COPD, with mean ± SD varying between 34.6 ± 8.5% and 44.9 ± 5.9%, increasing slightly with increasing inhalation duration (i.e., from 1 to 3 seconds), whereas extrathoracic deposition decreased progressively. Central deposition was low (<5%) regardless of inhalation duration (2.7 ± 0.9% to 4.4 ± 1.6%). Distal deposition was similar with the two tanimilast doses and although not impacted by inhalation duration was slightly higher in COPD than asthma. Peripheral deposition increased with increasing inhalation duration (e.g., in asthma for tanimilast 400 µg, from 14.1 ± 3.6% for a duration of 1 second to 19.9 ± 4.0% for a duration of 3 seconds) and was higher in asthma than in COPD. Conclusions: Tanimilast effectively reached all levels of the airway in patients with asthma or COPD. Peripheral deposition was enhanced by lower inspiratory flows (i.e., longer inhalation durations), suggesting that specific inhalation strategies may have the potential to improve therapeutic outcomes in obstructive lung diseases.

ABSTRACT The development of nanocarriers for nucleic acid delivery has gained significant attention as a promising strategy to regulate protein expression. Small interfering RNA (siRNA) is a powerful tool for gene silencing; however, it is rapidly degraded in the human body and cannot passively cross cell membranes due to its size and strong negative charge. To protect siRNA and facilitate intracellular delivery, a spermine‐based polyacrylamide with a hydrophobic side chain was utilized as a carrier system. This polymer demonstrated high encapsulation efficiency, forming nanoparticles below 150 nm in size with a slightly positive zeta potential and low polydispersity at N/P ratios of 5 and 7. Additionally, the formulation process proved to be highly reproducible and scalable using a microfluidic mixing method. Moreover, siRNA‐polyplexes exhibited good biocompatibility and maintained high cell viability post‐transfection. In vitro, they demonstrated strong knockdown efficiency in murine fibroblasts (L929), murine lung epithelial cells (MLE12), human lung adenocarcinoma cells (A549), and human cervix adenocarcinoma cells (HeLa‐GFP). Furthermore, the polyplexes promoted rapid cellular uptake and efficient endosomal escape, ensuring effective intracellular delivery. Given the therapeutic potential of siRNA, particularly for diseases lacking effective treatments, this approach holds significant promise for targeting solid tumors and fibrotic disorders.

BackgroundIn patients with uncontrolled asthma treated with medium dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA), the Global Initiative for Asthma (GINA) recommends to increase to high-dose ICS/LABA or to start therapy consisting of medium-dose ICS/LABA+LAMA (long-acting muscarinic antagonist). Adding LAMA on top of high-dose ICS/LABA is not recommended for Step 4 asthma patients, yet it is used in the real world. Patient characteristics influencing treatment step-up are unknown. The objectives of the present study were to identify determinants of step-up option (high-dose ICS/LABA, medium-dose ICS/LABA+LAMA, high-dose ICS/LABA+LAMA) in patients with moderate to severe asthma.MethodsA retrospective cohort study using three primary care databases (IPCI, HSD, CPRD GOLD) and one prescription database (Aarhus) included asthma patients with step-up after ≥3 months use of medium-dose ICS/LABA, from January 2010 to April 2020. Characteristics of patients were described, and determinants of choice for medium-dose ICS/LABA+LAMA or high dose ICS/LABA were investigated.Results492 639 adults with asthma and ≥1 year of database history were identified and 25 558 were eligible for analysis. 6126 patients stepped-up to medium-dose ICS/LABA+LAMA and 18 947 patients stepped-up to high-dose ICS/LABA. Determinants for step-up to medium-dose ICS/LABA+LAMA were higher age and presence of COPD whereas history of atopy lowered this choice. Other covariates were differentially associated with specific treatment step-up depending on the databases.ConclusionIn uncontrolled asthma patients on medium-dose ICS/LABA, treatment step-up with add-on LAMA was more likely than step-up to high-dose ICS/LABA in older patients, current smokers, with a history of asthma exacerbations and concomitant diagnosis of COPD.

Abstract Introduction: Premature-born individuals face a higher risk of respiratory morbidity, asthma-like symptoms, and COPD. Whether adult preterm-born individuals with asthma and COPD are aware of this fact and whether this information is discussed with their healthcare professionals (HCPs) along their healthcare journey is unknown. Methods: This was an online survey self-administered by adult preterm-born individuals diagnosed with asthma or COPD from France, Spain, Germany, the UK, and the US. The survey was available through an online patient platform (Carenity, https://pro.carenity.com) between March and July 2024 and consisted of 34 questions divided into a) screening questions, b) medical profile and preterm awareness, and c) patient care journey. Preterm-born individuals were recruited via Carenity's platform and Patient Advocacy Organizations (European Foundation for the Care of Newborn Infants [EFCNI] and Adult Preemies Advocacy Network). Results: 3,175 individuals started the survey. After exclusions, 301 questionnaires (9.5%) were considered valid. Most participants were women (74%), median age was 55 years (range 20-80), 44.5% had asthma, 26% COPD, 16% asthma+COPD overlap, and 14% had other chronic respiratory conditions. Most participants (87%) knew their preterm status, and 81% knew their medical history, mainly from discussions with relatives (38% were born very to extremely preterm [≤32 weeks’ gestation], and 49% moderate to late preterm [&amp;gt;32 weeks]). 58% declared they received specific care at birth. Of these, 67% required an incubator, and 17% stayed in the hospital for more than a month. Assisted ventilation was reported by 35%. During childhood, 46% of respondents were monitored regarding their preterm status, whereas 54% were not monitored or did notrecall any monitoring. Half of the respondents (54%) believe that preterm status should be considered when managing their respiratory condition, but only one-third have shared their preterm status with their current HCP (Figure 1). The consideration of preterm birth by HCPs is limited, as half of the responders reported that they were not asked about, and when it was disclosed, third of providers did not react to this information. Conclusion: Most preterm-born adults with chronic respiratory conditions are aware of their preterm status. While they do not tipically link prematurity to the type, severity, or management of their condition. Despite this, they perceive prematurity as having a moderate lifelong impact on their health, indicating that it should be considered in their care. Neverhless, HCPs reportedly give limited attention to the patients'preterm status.

Recent and emerging environmental policies have boosted the investigation of pressurized metered-dose inhalers (pMDI) that have a minimal impact on climate change. There is a current move away from existing hydrofluorocarbon (HFC)-based propellants, specifically the hydrofluoroalkane (HFA)-134a and HFA-227ea based pMDI products that are approved for the treatment of asthma and chronic obstructive pulmonary disease (COPD), towards those that use low global warming potential (LGWP) propellants. Changing the propellant to, for example, the less environmentally-damaging HFA-152a, is a focus for many manufacturers. In this paper, we report an innovative approach to developing new pMDI drug products with a LGWP propellant. Moreover, proof of the hypothesis that products containing the current propellant and those using a LGWP propellant can achieve equivalent performance is reported, by showing comparability of a triple combination pMDI (Trimbow®) formulated using the LGWP HFA-152a propellant compared with HFA-134a. This paper will present the use of in silico mathematical modelling, leveraging on Chiesi proprietary Modulite® principles to predict and validate in vitro performances of the drug product under development. Validation is carried out using realistic aerodynamic particle size distribution (rAPSD), a novel approach that offers a more accurate prediction of aerosol distribution by incorporating variations compared to the standard aerodynamic particle size distribution (APSD). Additional in vitro testing validates the prediction of in silico models and confirms good comparability in terms of aerodynamic performance between HFA-152a and HFA-134a, which translates in vivo as evidenced by the preliminary pharmacokinetics (PK) in animal models and the formal clinical PK bioequivalence (BE) studies. (Rony et al. in Pulm Pharmacol Ther 85, 2024).Graphical

Lipodystrophy syndromes are rare disorders characterized by deficient adipose tissue, leading to insulin resistance, dyslipidemia, and organ system abnormalities. Our goal was to develop a lipodystrophy severity score (LDS) to holistically capture the diverse manifestations of lipodystrophy into a numerical score to aid in prediction of clinical outcomes and/or treatment impact. An 8-domain LDS was developed by 8 disease experts in consultation with patient organizations. The LDS was rated for feasibility and content validity by 28 additional clinicians and 9 patient representatives. LDS was compared to the Clinical Global Impression (CGI) of severity for 20 putative patient profiles, each at 2 different time points, and by comparing change in LDS to global impression of change. For external validation, LDS was calculated in 2 cohorts of patients with lipodystrophy treated with metreleptin. LDS domains include Diabetes/Insulin Resistance, Microvascular Complications of Diabetes, Lipids, Cardiovascular, Liver, Kidney, Reproductive, and Other. Each domain is assessed by 1 or more questions assessing both lifetime and recent complications of lipodystrophy. The LDS had high content validity and feasibility and high reliability by intraclass correlation coefficients (>0.95). Global and domain-specific LDS were strongly correlated with CGI, as were changes in scores across visits (R = 0.79-0.99, P < .001 for all). In generalized lipodystrophy, metreleptin significantly reduced LDS (from 46 to 26 at 12 months, P < .001). The reductions were smaller in partial lipodystrophy (from 65 to 61 at 12 months, P = .04). The LDS can reflect the severity of diverse manifestations of lipodystrophy and monitor changes following interventions.