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Global Use of Casein Glycomacropeptide Protein Substitutes for Phenylketonuria (PKU): Health Professional Perspectives
No full textBackground/Objectives: Casein glycomacropeptide (cGMP) has been modified to enable its suitability as a low phenylalanine (Phe) protein substitute (PS) in phenylketonuria (PKU). No data is available about its global usage. Methods: A 60-item multiple choice and short answer/extended response questionnaire examining the use of modified cGMP in PKU was distributed globally to dietitians and physicians via web-based professional inherited metabolic disorder groups. Results: Respondents (n = 208) from 45 countries across 6 continents completed the questionnaire. Of these, 83.7% (n = 174) were dietitians/nutritionists, 14.9% (n = 31) medical doctors/physicians and 1.4% (n = 3) other health professionals, caring for both paediatric and adult patients (59.1%), paediatrics only (25.0%) or adults only (15.9%). cGMP PS were reported as not available in their centre/hospital by 19.7% (n = 41), mostly in Africa, South America, and southern and western Asia. The main reasons included lack of regulatory approval (65.8%), not promoted by manufacturers (41.5%), and cost (29.3%). An estimated 25% of represented patients globally were using cGMP PS; 78.4% (n = 163) following refusal/poor adherence with Phe-free amino acids and 54.8% (n = 114) for adult patients recommencing dietary treatment. There were concerns about the residual Phe in cGMP negatively impacting blood Phe levels in children <12y (66.3%), adolescents (48.0%), adults (34.6%), and the first trimester of pregnancy (53.1%). Sixty nine percent (n = 145) adjusted dietary Phe prescription according to the cGMP Phe content, particularly in regions with a higher percentage of severe PKU variants. Commonly perceived clinical advantages with cGMP were improved taste/palatability (93.2%, n = 194) and fewer gastrointestinal symptoms (55.8%, n = 116). Perceived clinical disadvantages were residual Phe (72.1%, n = 150), lack of data in children < 3 years (48.1%, n = 100), and the high energy content of some brands (45.2%, n = 94). There were concerns that cGMP PS were too high in sugar (34.1%, n = 71) and dissatisfaction or uncertainty about the adequacy of its Phe (66.3%) and amino acid (34.1%) content. Conclusions: There is global inconsistency in access to cGMP PS suitable for PKU, and in the interpretation of evidence-based research. Some professionals have significant concerns about its nutritional composition particularly residual Phe, limiting its estimated use to approximately 25% of PKU patients globally
Wolf Creek XVIII Part 3: Innovations in Defibrillation Science
No full textIntroduction: Effective defibrillation lies at the heart of successful resuscitation of ventricular fibrillation cardiac arrest. Can it be done better? Methods: The 50th Anniversary Wolf Creek XVIII Conference was hosted by the Max Harry Weil Institute for Critical Care Research and Innovation in Ann Arbor, Michigan, USA on June 19-21, 2025. Since its inception in 1975, the Wolf Creek Conference has a well-established tradition of providing a unique forum for robust intellectual exchange between thought leaders and scientists from academia and industry focused on advancing the science and practice of cardiac arrest resuscitation. Results: Innovations in Defibrillation Science was one of six focused panel topics that was presented and discussed by invited panelist and conference participants as recognized thought leaders in the field of cardiac arrest resuscitation, all of whom completed conflict of interest disclosures.The presentations by invited panelist and discussion focused on four distinct defibrillation-related topics, each written as was presented by its contributing author, providing their individual perspectives. Where applicable, each discussion addressed the current state, potential future state, knowledge gaps, barriers to translation, and research priorities in defibrillation science. Topics included refining the definition of defibrillation and resuscitation success, describing defibrillation mechanisms, double sequential external defibrillation for refractory ventricular fibrillation, and use of quantitative waveform analysis to better direct resuscitation care. Conclusions: Although much is known, much remains to be learned about defibrillation and its optimal application during resuscitation of cardiac arrest
Cesarean delivery for placenta previa
No full textPlacenta previa is an absolute indication for cesarean delivery and is associated with serious risks for maternal and neonatal health. At delivery, its prevalence is 0.5% to 1%, after being observed in up to 10% at the mid-trimester scan. Risk is highest with prior cesarean delivery and recurrence after a prior placenta previa is 4% to 8%. Twin gestations have a higher absolute prevalence (3.9 vs 2.8 per 1000 live births), and assisted reproduction carries a 6-fold risk compared to spontaneous conception. Maternal morbidity is dominated by hemorrhage: antepartum bleeding occurs in 40% to 60% and postpartum hemorrhage in 20% to 35%. Preterm birth drives neonatal risk: more than 40% of patients with placenta previa deliver before 37 weeks, and placenta previa accounts for 6% to 7% of indications for delivery before 35 weeks. Transvaginal ultrasound is the diagnostic gold standard and should be used to confirm transabdominal findings, measure the internal os distance, and exclude associated conditions (placenta accreta spectrum and vasa previa). Antenatal management and timing of delivery are based on the delicate equilibrium between the risk of maternal hemorrhage and the consequences of iatrogenic prematurity. For asymptomatic placenta previa, planned cesarean is generally recommended at 360 to 376 weeks (often earlier within this window for anterior previa). For low-lying placenta, internal-os distance guides delivery planning and current evidence supports a trial of labor in women with a distance of 11 to 20 mm. Operative care should be standardized within a multidisciplinary "placenta team" (obstetrics, anesthesia, interventional radiology, and urology as needed), with preparedness for major hemorrhage. Given the psychological burden-especially in complicated cases-structured debriefing and postpartum support are recommended
Study of POLR3A variants in a family trio suggests mutation-specific pathogenetic mechanisms: insights from integrative OMIC approaches
No full textBackground: Hypomyelinating leukodystrophies (HLDs) are rare genetic neurodevelopmental disorders characterized by defective myelin formation. The genetic cause of these disorders has been ascribed to mutations in genes encoding myelin protein components, such as proteolipid protein 1 (PLP1) and myelin basic protein (MBP), or in genes encoding for transcription and translation-related proteins. Particularly, biallelic pathogenic variants in POLR3A, POLR3B, POLR3K, POLR3D, POLR1C lead to the insurgence of RNA Polymerase III (Pol III)-related HLDs (POLR3-HLDs). The molecular mechanisms linking Pol III dysfunction to hypomyelination remain largely elusive, though the main hypothesis is that impaired Pol III activity likely disrupts gene expression and cellular homeostasis processes critical for myelin development and lipid metabolism. Methods: In this study, we analyzed a family trio consisting of unaffected carrier parents and a proband affected by POLR3A-related HLD, carrying compound heterozygous variants (p.Phe601Tyr and p.Gly1358Arg). We investigated the structural and functional consequences of two POLR3A variants using protein modeling, functional assays and multi-omics profiling in subject-specific primary fibroblasts. Results: Structural analysis revealed alterations in DNA-binding regions and a likely impact on protein stability, whilst functional assays showed an impairment in cellular proliferation. Lipidomic and transcriptomic profiling revealed that p. Gly1358Arg mutation predominantly affects lipidomic metabolism, while p. Phe601Tyr was associated with a widespread transcriptional dysregulation. Both mutations ultimately caused a significant reduction in lipid droplets in the proband's cells. Conclusions: These results demonstrate mutation-specific pathogenetic mechanisms in POLR3A-HLD and underline the utility of integrative multi-omics approaches in elucidating the molecular basis of rare neurodevelopmental disorders
Elevated gamma activity in left frontotemporal regions preceding sleep signals emotional arousal in Bipolar Disorders: Insights from a high-density EEG investigation
No full textBackground While changes in sleep architecture during depression and mania are well-established, the extent to which they persist during euthymia in Bipolar Disorders (BD) remains unclear. Here we investigate pre-sleep cortical arousal and its correlation with sleep architecture and subjective sleep quality in BD patients. Methods Subjective sleep measures and whole–night, high–density sleep electroencephalography (EEG) recordings were obtained from 16 euthymic BD patients and 16 age and sex-matched healthy control subjects. Sleep architecture was determined according to standard guidelines and power analysis was computed to compare mean group 0.5–80 Hz frequency bands in the EEG signal preceding sleep onset. Results Despite the absence of disturbances in subjective sleep, euthymic BD patients exhibited heightened sleep onset latency (52,91 ± 60,3 vs 21,76 ± 29,71, p = 0,018), REM density (2,65 ± 1,47 vs 1,52 ± 1,17, p = 0,022), and poorer sleep efficiency (0,64 ± 0,15 vs 0,74 ± 0,21, p = 0,032) compared to healthy controls. Total sleep time and durations of sleep substages did not differ between the groups. Additionally, our findings revealed increased pre-sleep gamma power in left frontotemporal areas among BD patients ( p = 0.005), which exhibited an inverse relationship with sleep efficiency that approached significance ( r = −0.497, p = 0.050). Conclusion Our findings suggest an alteration in sleep onset, efficiency, and REM density in euthymic BD patients, in the context of a preserved sleep duration. Some of these changes may be associated with a neural signature of cortical arousal that influences sleep quality
Navigating political emotions and agency among italian youth in the post-pandemic urban landscape
No full textThis study explores attitudes toward civic involvement in public life in the post-
pandemic context, informed by recurring political emotions among young individu-
als between 16 and 26 years of age living in the metropolitan area of Milan and its
hinterland. Drawing on 66 in-depth interviews conducted between 2022 and 2024
with young participants, the article traces the political emotions of this generation of
under-30s in response to multiple crises and unpacks how the latter shape youth
preferences with regard to civic action. Focusing on the gray area of occasional
activists, the article highlights how the multiple crises of recent years have exacer-
bated feelings of exceptionalism, impotence, and intergenerational injustice, which
are translated into a preference for individualistic approaches to social change. At
the same time, the study unpacks how this socio-historical conjuncture encourages
new forms of voluntarism driven by compassion and motivated by widespread sen-
sitivity to social justice, gender issues, and climate change
Chemotaxis-Driven Instabilities Govern Size, Shape and Migration Efficiency of Multicellular Clusters
No full texthe collective chemotaxis of multicellular clusters is an important phenomenon in various physiological contexts, ranging from embryonic development to cancer metastasis. Such clusters often display interesting shape dynamics and instabilities, but their physical origin, functional benefits, and role in overall chemotactic migration remain unclear. Here we combine computational modeling and experimental observations of malignant lymphocyte cluster migration in vitro to understand how these dynamics arise from an interplay of chemotactic response and intercellular interactions. Our cell-based computational model incorporates active self-propulsion of cells, contact inhibition of locomotion, chemoattractant response, as well as alignment, adhesive, and exclusion interactions between cells. We find that clusters remain fluid and maintain cohesive forward migration in low chemoattractant gradients. However, above a threshold gradient, clusters display an instability driven by local cluster-shape dependent velocity differentials that causes them to elongate perpendicular to the gradient and eventually break apart. Comparison with our in vitro data shows the predicted transition to the cluster instability regime with increased gradient, as well as quantitative agreement with key features such as cluster aspect ratio, orientation, and breaking frequency. This instability naturally limits the size of multicellular aggregates, and, in addition, clusters in the instability regime display optimal forward migration speeds, suggesting functional implications in vivo. Our work provides valuable insights into generic instabilities of chemotactic clusters, elucidates physical factors that could contribute to metastatic spreading, and can be extended to other living or synthetic systems of active clusters
GY971 mitigates inflammation by reducing neutrophil recruitment in cystic fibrosis Ex Vivo and In Vivo models
No full textBackground There is a prominent need for anti-inflammatory agents for people with Cystic Fibrosis (pwCF), even in the era of CFTR modulators. ETI (Elexacaftor/Tezacaftor/Ivacaftor) reduces but does not eliminate pulmonary inflammation, that chronically damages CF pulmonary tissues and favors recurrent pulmonary exacerbations. Furthermore, although known anti-inflammatory drugs are beneficial to pwCF, their side effects are limiting the clinical use. To address this issue, we developed a new synthetic furocoumarin molecule named GY971, able to reduce the excessive accumulation of neutrophils in the bronchial lumen, by targeting the NF-κB transcription factor (TF). Methods To assess its efficacy, GY971 was tested in human primary bronchial and nasal epithelial cells obtained ex vivo from different pwCF carrying the F508del mutation and infected with Pseudomonas aeruginosa . Moreover, GY971 was also administered in a zebrafish model infected with P. aeruginosa in vivo . Results GY971 reduced neutrophil chemotaxis mediators both in CF bronchial epithelial cell lines and in CF primary bronchial and nasal epithelial cells ex vivo . The expression of key inflammatory proteins involved in CF lung disease, including IL-8, IL-1β, TNF-α and IL-6, was significantly reduced using nanomolar concentrations of GY971. Importantly, GY971 does not interfere with the ETI-mediated rescue of CFTR protein and showed no cytotoxic effects. Lastly, in vivo testing with a zebrafish model confirmed its effectiveness: GY971 decreased neutrophil recruitment in treated larvae across different concentrations, supporting earlier results from murine studies. Conclusions GY971 appears to be a promising molecule for the future development of combinatorial anti-inflammatory treatments together with ETI
Baseline clinical profile of patients with obstructive hypertrophic cardiomyopathy in the Italian Mavacamten early access program
No full textBackground: Obstructive hypertrophic cardiomyopathy (oHCM) has recently seen the introduction of mavacamten, a disease-specific therapy that alleviates obstruction and symptoms with potential effects on disease expression. Since most patients remain symptomatic with conventional therapies, mavacamten constitutes an efficacious treatment strategy METHODS: The early access program (EAP) for mavacamten treatment ran from September 2023 to September 2024. We collected clinical and echocardiographic data prospectively RESULTS: 337 patients with oHCM (53% male, mean age 61.4 ± 12.3 years) were receiving mavacamten treatment from 54 centers in Italy. The EAP cohort was older and showed a more advanced cardiac phenotype, showing lower left ventricular ejection fraction (LVEF) (66 ± 6% vs 74 ± 6% in EXPLORER-HCM cohort, p < 0.0001) and higher left atrial volume index (51.1 ± 16.4 ml/m2 vs 40.5 ± 12.3 ml/m2, p < 0.0001. Only 74 (22%) patients in the EAP group were candidates for septal reduction therapy (SRT). Echocardiographic parameters like LVEF, maximal wall thickness and LAVI as well as pharmacologic therapy showed no difference between subgroups, while LVOT obstruction gradient was higher in SRT candidates (40 vs 63 mmHg, p < 0.0001).. Conclusion: The compassionate use program for mavacamten in Italy demonstrated significant engagement. The Italian oHCM cohort were older and exhibited more advanced disease stages compared to those in the EXPLORER-HCM trial. Only one-quarter of the patients were eligible for SRT, they did not show a more severe biomarker or echocardiographic parameters compared to those without indication. Mavacamten provides an additional option for oHCM patients unresponsive to standard therapy, especially those symptomatic but ineligible for SRT
Prognostic significance implications of aortic valve sclerosis in the development of aortic stenosis: a systematic review and meta-analysis
No full textBackground Fibrocalcific aortic valve sclerosis (AVSc), the earliest manifestation of aortic stenosis (AS), is increasingly recognised as a marker of systemic vascular damage and adverse cardiovascular outcomes. While a subset of AVSc patients progresses to AS, reported rates vary widely. We conducted a systematic review and meta-analysis to better define the natural history of AVSc progression. Methods Following Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, we searched PubMed, Scopus and Web of Science through July 2025 for observational studies reporting AS development in AVSc patients. Primary outcomes were progression to any degree of AS and to severe AS. Pooled event rates were calculated using a random-effects model. Heterogeneity and publication bias were assessed using standard statistical methods. Meta-regression explored associations with clinical and demographic variables. Results Eight studies (n=12388 patients) reported on the progression of AVSc patients to any AS stage, and nine studies (n=19486 patients) on the progression to severe AS. Over a median follow-up of 4.0 years, 14.1% of AVSc patients progressed to any AS stage (effect size: 0.14; 95%CI 0.02 to 0.53), and 2.0% to severe AS (effect size: 0.02; 95%CI 0.003 to 0.094). Heterogeneity was high, but no publication bias was detected. Meta-regression found no significant predictors of progression. Conclusions Approximately one in six AVSc patients progresses to AS within 4 years, and 2% develop a severe disease. These findings underscore the importance of structured echocardiographic surveillance and support AVSc as a clinically relevant marker of systemic cardiovascular risk