Acai Oil-Based Organogel Containing Hyaluronic Acid for Topical Cosmetic: In Vitro and Ex Vivo Assessment.

Organogels are semi-solid pharmaceutical forms whose dispersing phase is an organic liquid, for example, an oil, such as acai oil, immobilized by a three-dimensional network formed by the gelling agent. Organogels are being highlighted as innovative release systems for cosmetic active ingredients such as hyaluronic acid for topical applications. Acai oil was evaluated for its physicochemical parameters, fatty acid composition, lipid quality index, spectroscopic pattern (Attenuated total reflectance Fourier Transform Infrared Spectroscopy), thermal behavior, total phenolic, total flavonoids, and total carotenoids and ß-carotene content. The effectiveness of the organogel incorporated with hyaluronic acid (OG + HA) was evaluated through ex vivo permeation and skin retention tests, in vitro tests by Attenuated total reflectance Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry. The physicochemical analyses highlighted that the acai oil exhibited quality standards in agreement with the regulatory bodies. Acai oil also showed high antioxidant capacity, which was correlated with the identified bioactive compounds. The cytotoxicity tests demonstrated that the formulation OG + HA does not release toxic substances into the biological environment that could impede cell growth, adhesion, and efficacy. In vitro and ex vivo analyses demonstrated that after 6 h of application, OG + HA presented a high level of hydration, thermal protection and release of HA. Thus, it can be concluded that the OG + HA formulation has the potential for physical-chemical applications, antioxidant quality, and potentially promising efficacy for application in the cosmetic areas.

Iron capture through CD71 drives perinatal and tumor-associated Treg expansion.

Besides suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss. In perinatal life, CD71 deficiency in Tregs triggered hepatic iron overload response, characterized by increased hepcidin transcription and iron accumulation in macrophages. Lower bacterial diversity, and reduction of beneficial species, were detected in the fecal microbiota of CD71 conditional knockout neonates. Our findings indicate that CD71-mediated iron absorption is required for Treg perinatal expansion and is related to systemic iron homeostasis and bacterial gut colonization. Therefore, we hypothesize that Tregs establish nutritional tolerance through competition for iron during bacterial colonization after birth.

Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants.

BACKGROUND: Variants in GABRB2, encoding the ß2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants. METHODS: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. FINDINGS: Electrophysiological assessments of α1ß2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. INTERPRETATION: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. FUNDING: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

Spray-Drying Microencapsulation of Bauhinia ungulata L. var. obtusifolia Aqueous Extract Containing Phenolic Compounds: A Comparative Study Using Different Wall Materials.

Species belonging to the Bauhinia genus, usually known as "pata-de-vaca", are popularly used to treat diabetes. Bauhinia ungulata var. obtusifolia (Ducke) Vaz is among them, of which the leaves are used as a tea for medicinal purposes in the Amazon region. A microencapsulation study of lyophilized aqueous extract from Bauhinia ungulata leaves, which contain phenolic compounds, using five different wall materials (maltodextrin DE 4-7, maltodextrin DE 11-14; ß-cyclodextrin; pectin and sodium carboxymethylcellulose) is described in this paper. The microstructure, particle size distribution, thermal behavior, yield, and encapsulation efficiency were investigated and compared using different techniques. Using high-performance liquid chromatography, phenolics, and flavonoids were detected and quantified in the microparticles. The microparticles obtained with a yield and phenolics encapsulation efficiency ranging within 60-83% and 35-57%, respectively, showed a particle size distribution between 1.15 and 5.54 µm, spherical morphology, and a wrinkled surface. Among them, those prepared with sodium carboxymethylcellulose or pectin proved to be the most thermally stable. They had the highest flavonoid content (23.07 and 21.73 mg RUTE/g Extract) and total antioxidant activity by both the DPPH (376.55 and 367.86 µM TEq/g Extract) and ABTS (1085.72 and 1062.32 µM TEq/g Extract) assays. The chromatographic analyses allowed for quantification of the following substances retained by the microparticles, chlorogenic acid (1.74-1.98 mg/g Extract), p-coumaric acid (0.06-0.08 mg/g Extract), rutin (11.2-12.9 mg/g Extract), and isoquercitrin (0.49-0.53 mg/g Extract), compounds which considered to responsible for the antidiabetic property attributed to the species.

Motor Development of Children in the Kurdistan Region of Iraq: Parent Survey.

The actual literature highlights the importance of the socio-cultural context in the development of children. However, there is a lack of specific evidence about the middle East, especially regarding the development of Kurdish children who are living in a post-war scenario, in a country which is experiencing continuous instability due to the different crises. The main aim of this study is to identify the features of the motor development of Kurdish children according to parents' opinion. A comparison with Italian children is provided as a Western example, which reflects data from the literature. In the study, 331 parents of Kurdish and Italian children aged between 3 and 7 years were involved. Parents filled the questionnaire at kindergartens, after providing consent. The questionnaire was conceptualized, designed, tested and provided ad hoc for this study; it focused on the timing of development, concerning major milestones like head control, sitting and standing-up. The questionnaire consists of 15 questions and has not been standardized yet. A logistic regression showed several differences between Kurdish and Italian children, like head control (p = 0.007) or the manipulation of big objects (p < 0.0001). These results identify the effect of the socio-cultural context and the impact of the growing environment of the child. Moreover, the results of this survey show the need for introducing different adapted, translated and validated assessment tools for motor development, considering differences related to the socio-cultural context.

Adult Phenotype of SYNGAP1-DEE.

Background and Objectives: SYNGAP1 variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although SYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with SYNGAP1 variants and epilepsy. Methods: Patients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P) SYNGAP1 variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden. Results: Fourteen unrelated adult patients (median: 21 years, range: 18-65 years) with SYNGAP1-DEE were identified, 11 with novel and 3 with known LP/P SYNGAP1 de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger. Discussion: Seventy-one percent of patients with SYNGAP1-DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults with SYNGAP1-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.

Real life data on nintedanib safety: idiopathic pulmonary fibrosis versus systemic sclerosis-interstitial lung disease and strategies adopted to manage adverse effects.

OBJECTIVE: Nintedanib (NIN) is an antifibrotic drug approved to slow the progression of idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-related interstitial lung disease (SSc-ILD). NIN can frequently cause gastrointestinal adverse effects. We aimed to investigate the NIN safety profile in a real life setting, comparing IPF and SSc-ILD patients and evaluating the strategies adopted to manage NIN adverse effects. METHODS: Patients taking NIN for IPF or SSc-ILD were enrolled. Alongside epidemiological and disease-specific data, the period of NIN use and the need for dosage reduction and/or interruption were investigated. Particular attention was paid to possible adverse effects and strategies adopted to manage them. RESULTS: Twenty-seven SSc-ILD and 82 IPF patients were enrolled. No significant differences emerged between the two cohorts regarding the frequency of any possible adverse effect. Although the rates of NIN dosage reduction or interruption were similar between the two subgroups, SSc-ILD presented a mean period before NIN dosage reduction and NIN interruption significantly shorter than IPF (3 ± 2.6 vs 10.5 ± 8.9 months-p < 0.001 and 2.3 ± 0.5 vs 10.3 ± 9.9 months-p = 0.008, respectively). Several different strategies were tried to manage NIN adverse effects: especially in SSc-ILD, the variable combination of diet adjustment set by a nutritionist, probiotics and diosmectite was ultimately successful in maintaining patients on an adequate dose of NIN. CONCLUSION: We presented data on the NIN safety profile in a real life setting, which was similar between SSc-ILD and IPF. A combination of multiple managing strategies and dose adjustment appears essential to cope optimally with NIN adverse effects.

KIRREL3-related disorders: a case report confirming the radiological features and expanding the clinical spectrum to a less severe phenotype.

BACKGROUND: Neurodevelopmental disorders have a multifactorial etiology, since biological, genetic, psychosocial and environmental risk factors are involved. Recent studies have been linking neurodevelopmental disorders and intellectual disability with a variety of genes, some of which encoding neuronal cell-adhesion molecules. Among these, KIRREL3 is known to play a role in CNS development, and his variants have recently been related to intellectual disability, autism spectrum disorder, childhood apraxia of speech, cerebellar hypoplasia and mild dysmorphic features. CASE PRESENTATION: In this study, we describe a young Caucasian boy with mild intellectual disability, cerebellar anomalies (cerebellar hypoplasia and mega cisterna magna) and minor dysmorphic features associated to a novel KIRREL3 variant. CONCLUSIONS: Aim of the present case report is to expand the clinical spectrum of KIRREL3-related diseases towards a milder phenotype than what is already described in the literature. We speculate that the interaction between KIRREL3 and CASK might play a major role in promoting cognitive and cerebellar development, contributing to a variety of clinical manifestations.

Identification of Proteins Involved in Cell Membrane Permeabilization by Nanosecond Electric Pulses (nsEP).

The study was aimed at identifying endogenous proteins which assist or impede the permeabilized state in the cell membrane disrupted by nsEP (20 or 40 pulses, 300 ns width, 7 kV/cm). We employed a LentiArray CRISPR library to generate knockouts (KOs) of 316 genes encoding for membrane proteins in U937 human monocytes stably expressing Cas9 nuclease. The extent of membrane permeabilization by nsEP was measured by the uptake of Yo-Pro-1 (YP) dye and compared to sham-exposed KOs and control cells transduced with a non-targeting (scrambled) gRNA. Only two KOs, for SCNN1A and CLCA1 genes, showed a statistically significant reduction in YP uptake. The respective proteins could be part of electropermeabilization lesions or increase their lifespan. In contrast, as many as 39 genes were identified as likely hits for the increased YP uptake, meaning that the respective proteins contributed to membrane stability or repair after nsEP. The expression level of eight genes in different types of human cells showed strong correlation (R > 0.9, p < 0.02) with their LD50 for lethal nsEP treatments, and could potentially be used as a criterion for the selectivity and efficiency of hyperplasia ablations with nsEP.

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum.

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Role of Low-FODMAP diet in functional dyspepsia: "Why", "When", and "to Whom".

Functional dyspepsia (FD) is a frequent disorder of gut-brain interaction, affecting 5-7% of people globally, with significant impairment in quality of life. The management of FD is challenging due to the lack of specific therapeutic approaches. Although food seems to play a role in symptom production, its pathophysiologic role in patients with FD is not fully understood. Most FD patients report that their symptoms are triggered by food, especially in the post-prandial distress syndrome (PDS) group, although evidence to support the use of dietary interventions are limited. FODMAPs can increase production of gas in the intestinal lumen, through fermentation by intestinal bacteria, can exert osmotic effects by increasing water volume and can cause an excessive production of short-chain fatty acids (propionate, butyrate, and acetate). Emerging scientific evidence, confirmed by recent clinical trials, suggest that FODMAPs could be involved in the pathogenesis of FD. Given the consolidated approach of the Low-FODMAP Diet (LFD) in irritable bowel syndrome (IBS) management and emerging scientific evidence regarding the LFD in FD, a therapeutic role of this diet may be hypothesized also in FD, either alone or in combination with other therapies.

Understanding the factors affecting the quantity and composition of street litter: Implication for management practices.

Some urban areas have more litter than others. Understanding the reason for this is important not only for dealing with urban littering but also for marine water quality because approximately 80% of the world's marine litter originates on land. This study aimed to better understand the quality and quantity of litter on sidewalks along with the sampling site's socio-economic attributes to better discern why some areas have more/different litter than others and what, if any, are the implications for a more tailored waste management strategy. We surveyed twice each of the 35 sites we selected from the Lower Passaic River watershed and the related Harbor Estuary within New Jersey, U.S.A. A total of 28,431 litter items were recorded with a total mass and volume of 245.8 kg and 4.7 m3, respectively. Floatable items accounted for 66% of all objects collected. Cigarette butts were the most numerous among all items (28%) and represented 43% of the total floatable items, the remaining 57% being represented by potentially recyclable items such as plastic, rubber, and Styrofoam. Stepwise linear regression was used to explore the relationship between the litter collected and various predictors. Among others, the results suggest the importance of strategically placing collection bins around properties with relatively lower assessed values, outdoor smoking areas, close to schools, and places where people predominantly walk to their destination. Possible management strategies include prohibiting single use plastic bags, limiting foam food ware, public education, and outreach.

The role of blood cholesterol quality in patients with advanced cancer receiving immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) became the standard of care for several solid tumors. A limited fraction of patients (pts) achieves a long-term benefit. Plasmatic and intracellular cholesterol levels have emerged as promising biomarkers. The aim of the present study was to determine whether cholesterol efflux capacity (CEC), mediated by serum transporters (ABCA1 and ABCG1) and passive diffusion (PD), impacts on clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs. MATERIAL AND METHODS: We retrospectively enrolled advanced NSCLC and mRCC pts consecutively treated with ICIs between October 2013 and October 2018. CEC and cholesterol loading capacity (CLC) were assessed by well-established specific cell models. As primary endpoint, CEC, PD and CLC were correlated with overall survival (OS) while the effects of these parameters on progression-free survival (PFS) and clinical benefit (CB), defined as complete/partial response or stable disease, represented secondary endpoints. RESULTS: NSCLC accounted for 94.2% of 70 enrolled cases, and serum sample suitable for CEC and PD determination was available in 68. Blood cholesterol and serum ABCA1, ABCG1, PD and CLC were associated with outcomes (OS, PFS and CB) at univariate analysis. At the multivariate analysis, only PD confirmed its positive prognostic value in terms of OS, PFS and CB. CONCLUSION: The favorable impact of cholesterol PD on clinical outcome might reflect its main conformation in mature HDL particles which potentially shape an inflamed context, ultimately promoting ICI efficacy. Further prospective studies are needed to support our findings and uncover targetable pathways.

Adaptation, Validity, and Reliability of the Patient Health Questionnaire (PHQ-9) in the Kurdistan Region of Iraq.

AIM: The Patient Health Questionnaire (PHQ-9) is widely used for detecting and screening depression in Iraq. However, no psychometric assessment has been performed on any Iraqi version. This study aims at studying the reliability and validity of the Iraqi Kurdish version of the PHQ-9 as tool for identifying depression. METHODS: A cross-sectional study design was used; data were collected from 872 participants (49.3% female and 51.7% male) at Primary Health Care Centers (PHCCs) in the host community as well as from Internal Displaced Persons (IDPs) and refugee camps. Sociodemographic information was obtained; PHQ-9 for the diagnosis and screening of depression and Self Reporting Questionnaire 20 items (SRQ-20) for the screening of common mental illnesses were administered. Validity and reliability analyses were performed. RESULTS: In total, 19% of the participants had a PHQ-9 total score equal to or higher than the clinical cut-off of 10 for diagnosing depressive disorder. The internal consistency of the PHQ-9 was good (Cronbach's alpha coefficient was 0.89). Good concurrent validity for PHQ-9 compared with SRQ-20 (71%, p < 0.001) was found. CONCLUSIONS: The PHQ-9 demonstrates good psychometric properties and proves to be a good tool for detecting and screening depression.

The different clinical facets of SYN1-related neurodevelopmental disorders.

Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.

Clinical Features and Efficacy of Benralizumab in Patients with Blood Eosinophil Count Between 300 and 450 Cells/mm3: A Post Hoc Analysis from the ANANKE Study.

Purpose: Benralizumab effectively reduces severe eosinophilic asthma (SEA) exacerbations in patients with a wide range of baseline blood eosinophil count (BEC). Patients included in real-world studies are often characterized by high mean/median BEC, while patients with BEC close to 300 cells/mm3 are poorly represented. This post hoc analysis from the Italian study ANANKE aims to define the clinical features and corroborate the efficacy of benralizumab in real world in the BEC 300-450 cells/mm3 subset of patients. Patients and Methods: Post hoc analysis of the Italian, multicenter, observational, retrospective real-life study ANANKE (NCT04272463). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment and presented for a BEC 300-450 cells/mm3 subgroup of patients. Change over time of BEC, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use at 16, 24 and 48 weeks after benralizumab introduction were collected. Results: A total of 164 patients were analyzed, 34 of whom with a BEC of 300-450 cells/mm3. This subgroup was more likely to be female (64.7%), with lower rates of severe exacerbations at baseline when compared to the total population (0.69 vs 1.01). After 48 weeks of benralizumab treatment, the BEC 300-450 subset showed similar reductions in AER (-94.8% vs -92.2%) and OCS use (median dose reduction of 100% in both groups), as well as improvement in ACT score (median scores 22.5 vs 22) and lung function (pre-BD FEV1: +200 mL vs +300 mL) when compared to the total population. No discontinuations for safety reasons were registered. Conclusion: At baseline, apart from lower severe exacerbation rate, the BEC 300-450 cells/mm3 subset of patients is comparable to the total population prescribed with benralizumab. In this real-life study, benralizumab is as effective in BEC 300-450 patients as in the total population.

Stromal and Immune Cell Dynamics in Tumor Associated Tertiary Lymphoid Structures and Anti-Tumor Immune Responses.

Tertiary lymphoid structures (TLS) are ectopic lymphoid organs that have been observed in chronic inflammatory conditions including cancer, where they are thought to exert a positive effect on prognosis. Both immune and non-immune cells participate in the genesis of TLS by establishing complex cross-talks requiring both soluble factors and cell-to-cell contact. Several immune cell types, including T follicular helper cells (Tfh), regulatory T cells (Tregs), and myeloid cells, may accumulate in TLS, possibly promoting or inhibiting their development. In this manuscript, we propose to review the available evidence regarding specific aspects of the TLS formation in solid cancers, including 1) the role of stromal cell composition and architecture in the recruitment of specific immune subpopulations and the formation of immune cell aggregates; 2) the contribution of the myeloid compartment (macrophages and neutrophils) to the development of antibody responses and the TLS formation; 3) the immunological and metabolic mechanisms dictating recruitment, expansion and plasticity of Tregs into T follicular regulatory cells, which are potentially sensitive to immunotherapeutic strategies directed to costimulatory receptors or checkpoint molecules.

Rational and practical considerations to guide a target product profile for patient-centric drug product development with measurable patient outcomes - A proposed roadmap.

The increasing awareness of acceptability and usability of pharmaceutical drug products by the patient as a key quality requirement continues to drive need for integrating patient centric drug product design into the pharmaceutical development process. The complex matrix of multiple drug product related decisions during the early drug development process often limits patient-centric drug product (PCDP) design options in the final commercial drug product development phase. To integrate the specific needs and perspectives of patients into drug development and product design process, a rational approach integrated into the complex development matrix is required from the start and weighs product development decision options accordingly. The aim of this work was to develop a roadmap for PCDP design in a multidisciplinary approach that leads to better usability, adherence and acceptance of the drug by patients via early integration into the development matrix. The proposed rational approach is based upon regulatory requirements and lessons learned from pediatric and geriatric drug development.

Case Report of a Massive Life-threatening Neonatal Thrombosis Treated With a Targeted, Goal-oriented Scheme of Urokinase.

BACKGROUND: Thrombotic events are severe, often under-diagnosed, complications occurring in newborn infants during their hospital stay. Currently, there is no consensus regarding the optimal treatment scheme for thrombolysis in neonates. OBSERVATIONS: We present the case of a newborn suffering from a life-threatening thrombosis. Diagnosis was suggested by a gradual increase of C-reactive protein, with repeatedly normal procalcitonin. Thrombosis was successfully and safely treated with a long scheme of 21 days of urokinase, supported by vascular ultrasound and d-dimer trend. CONCLUSIONS: Laboratory and ultrasound results may help in adjusting the duration of the thrombolytic treatment, allowing for longer therapeutic schemes that could optimize treatment success. In addition, our case may suggest a possible combined role of C-reactive protein and procalcitonin as an early diagnostic aid in neonatal thrombosis.