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IMPORTANCE: There are multiple approved systemic treatments for atopic dermatitis. Lebrikizumab is a newly licensed biologic medication that has been compared to placebo in clinical trials but not to other systemic treatments. OBJECTIVE: To compare reported measures of efficacy and safety of lebrikizumab to other systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Latin American and Caribbean Health Science Information database, the Global Resource of Eczema Trials database, and trial registries were searched from inception through November 3, 2023. STUDY SELECTION: Randomized clinical trials evaluating 8 or more weeks of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis. Titles, abstracts, and full texts were screened in duplicate. DATA EXTRACTION AND SYNTHESIS: Data were abstracted in duplicate and random-effects bayesian network meta-analyses were performed. Minimal important differences were used to define important differences between medications. Certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). The updated analysis was completed from December 13, 2023, to February 20, 2024. MAIN OUTCOME MEASURES: Efficacy outcomes were the Eczema Area and Severity Index (EASI), the Patient Oriented Eczema Measure (POEM) Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS) and were compared using mean difference (MD) with 95% credible intervals (CrI). Safety outcomes were serious adverse events and withdrawal due to adverse events. Other outcomes included the proportion of participants with 50%, 75%, and 90% improvement in EASI (EASI-50, -75, -90) and the proportion with success on the Investigator Global Assessment compared using odds ratios with 95% CrI. RESULTS: The study sample included 97 eligible trials, with a total of 24 679 patients. Lebrikizumab was associated with no important difference in change in EASI (MD, −2.0; 95% CrI, −4.5 to 0.3; moderate certainty), POEM (MD, −1.1; 95% CrI −2.5 to 0.2; moderate certainty), DLQI (MD, −0.2; 95% CrI −2.1 to 1.6; moderate certainty), or PP-NRS (MD, 0.1; 95% CrI −0.4, 0.6; high certainty) compared to dupilumab among adults with atopic dermatitis who were treated for up to 16 weeks. Dupilumab was associated with higher odds of efficacy in binary outcomes compared with lebrikizumab. The relative efficacy of other approved systemic medications was similar to that found by previous updates of this living study, with high-dose upadacitinib and abrocitinib demonstrating numerically highest relative efficacy. For safety outcomes, low event rates limited useful comparisons. CONCLUSIONS AND RELEVANCE: In this living systematic review and network meta-analysis, lebrikizumab was similarly effective to dupilumab for the short-term treatment of atopic dermatitis in adults. Clinicians and patients can use these comparative data to inform treatment decisions. more...

Noncoding RNAs (ncRNAs) play pivotal roles in the regulation of gene expression and represent a promising target for the development of new therapeutic approaches. Among these ncRNAs, microRNAs (miRNAs or miRs) are involved in the regulation of gene expression, and their dysregulation has been linked to several diseases such as cancers. Indeed, oncogenic miRNAs are overexpressed in cancer cells, thus promoting tumorigenesis and maintenance of cancer stem cells that are resistant to chemotherapy and often responsible for therapeutic failure. Here, we describe the design and synthesis of new small-molecule RNA binders able to inhibit the biogenesis of oncogenic miRNAs and target efficiently cancer stem cells. Through the biochemical study of their interaction with the target and thanks to intracellular assays, we describe the structure–activity relationships for this new series of RNA ligands, and we identify compounds bearing a very promising antiproliferative activity against cancer stem cells. more...

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3–90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain. more...

We implemented radio frequency-assisted electrostatic force microscopy (RF-EFM) to investigate the electric field response of biaxially strained molybdenum disulfide (MoS2) monolayers (MLs) in the form of mesoscopic bubbles, produced via hydrogen (H)-ion irradiation of the bulk crystal. MoS2ML, a semiconducting transition metal dichalcogenide, has recently attracted significant attention due to its promising optoelectronic properties, further tunable by strain. Here, we take advantage of the RF excitation to distinguish the intrinsic quantum capacitance of the strained ML from that due to atomic scale defects, presumably sulfur vacancies or H-passivated sulfur vacancies. In fact, at frequencies fRFlarger than the inverse defect trapping time, the defect contribution to the total capacitance and to transport is negligible. Using RF-EFM at fRF= 300 MHz, we visualize simultaneously the bubble topography and its quantum capacitance. Our finite-frequency capacitance imaging technique is noninvasive and nanoscale and can contribute to the investigation of time- and spatial-dependent phenomena, such as the electron compressibility in quantum materials, which are difficult to measure by other methods. more...

Background:To search for H. pyloriinfection and gastric precancerous lesions in cirrhotic patients is worthwhile when considering the high incidence of peptic ulcers and gastric cancer in these patients. We tested if gastric juice analysis allows to avoid unrewarding gastric biopsies. Methods:This prospective study enrolled consecutive patients with liver cirrhosis who underwent upper endoscopy with standard gastric biopsies. Real-time gastric juice analysis was performed with a specific device (EndoFaster®) that test ammonium concentration for H. pyloridiagnosis, and pH values to suspect extensive atrophy/metaplasia involving gastric body mucosa. Sensitivity, specificity, positive predictive value, negative predictive value (NPV), the overall accuracy, and the likelihood ratio were calculated for both H. pyloriinfection and extensive precancerous lesions on gastric mucosa. Results:A total of 78 cirrhotic patients (males: 55; mean age: 66 ± 12 years) were enrolled. When considering as positive EndoFaster®results when at least one of two (ammonium and pH levels) tests were positive, the NPVs were as high as 89% and 86%, respectively, to rule out H. pyloriand extensive precancerous lesions on gastric mucosa, with an overall accuracy of 83% and 74%. Conclusions:This study supports the evidence that real-time gastric juice analysis allows to avoid clinically unrewarding and potentially unsafe gastric biopsies in a definite portion of cirrhotic patients, but more data are needed. more...

Carbapenem-resistant Acinetobacter baumannii(CRAB) has emerged as a major global pathogen with limited treatment options1. No new antibiotic chemical class with activity against A. baumanniihas reached patients in over 50 years1. Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB2FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB2FGC as a tractable target for antimicrobial drug development. more...

The aviation accident investigation process includes the detailed examination of the aircraft wreckage, as well as the analysis of both primary and secondary elements of the aircraft structure. This requires examination of the wreckage at the accident site, and is followed by additional analysis, often driven by the first results on the field. Therefore, one of the most important tasks of investigators is to determine the sequence of events of the accident. This means that much evidence should be collected to accurately determine the order in which events occurred. With regard to construction materials involved, the interpretation of fracture surfaces can provide very important information. However, metallic and composite structures demonstrate very different behaviors during the operative service, from corrosion and fatigue to fire and combustion resistance. This paper performs a literature review on the identification of failure mode, damage and safety of polymer composite aircraft structures from a point of view that may be useful to aviation safety investigations, with the aim to provide suggestions for future research. more...

This paper presents an application of the functional resonance analysis method (FRAM) to the risk assessment of low-speed legs of a helicopter flight mission. A combination of low forward speed and a specific rate of vertical descent could lead to meet a region of the helicopter’s flight envelope that shall be avoided to prevent the vortex ring state, an aerodynamic phenomenon which could cause uncontrolled high rates of descent. A fully developed vortex ring state (VRS) is characterized by an unstable situation in which the helicopter experiences uncommanded pitch and roll oscillations, with a reduced or no collective authority, and a helicopter descent rate that may approach more than 5000 feet per minute. If the recognition of VRS signs is performed early by the pilot in a condition of sufficient altitude, then the required recovery may be performed. However, some mission legs require to descend close to the ground, as the case of a firefighting mission, in which one of the fundamental task requires to fill a tank with water. This type of mission has been selected as the case study of this paper, and a qualitative risk assessment is performed using FRAM. The model developed using FRAM is systemic, where both accidents and successes are seen to emerge in the system from combinations of normal variability. Moreover, the model is complex and non-linear, providing a complete overview of functions and tasks performed by the whole system and the related couplings. The paper presents the potential events related to the mission selected and provides results in terms of possible safety barriers. more...

Purpose: This study is to use a simple algorithm based on patient’s age to reduce the overall biological detriment associated with PET/CT. Materials and Methods: A total of 421 consecutive patients (mean age 64 ± 14 years) undergoing PET for various clinical indications were enrolled. For each scan, effective dose (ED in mSv) and additional cancer risk (ACR) were computed both in a reference condition (REF) and after applying an original algorithm (ALGO). The ALGO modified the mean dose of FDG and the PET scan time parameters; indeed, a lower dose and a longer scan time were reported in the younger, while a higher dose and a shorter scan time in the older patients. Moreover, patients were classified by age bracket (18–29, 30–60, and 61–90 years). Results: The ED was 4.57 ± 0.92 mSv in the REF condition. The ACR were 0.020 ± 0.016 and 0.0187 ± 0.013, respectively, in REF and ALGO. The ACR for the REF and ALGO conditions were significantly reduced in males and females, although it was more evident in the latter gender (all p< 0.0001). Finally, the ACR significantly reduced from the REF condition to ALGO in all three age brackets (all p< 0.0001). Conclusion: Implementation of ALGO protocols in PET can reduce the overall ACR, mainly in young and female patients. more...

La estadía en Unidad de Cuidados Intensivos (UCI) conlleva complicaciones físicas y cognitivas. Actualmente se desconoce la evolución funcional y de la calidad de vida durante la internación en sala de hospitalización general (SHG) luego del paso en UCI. more...

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.02.023 Byline: Mario Gaudino (a), Michele Serricchio (b), Paolo Tondi (b), Laura Gerardino (b), Angela Di Giorgio (b), Paolo Pola (b), Gianfederico Possati (a) Abstract: Only scant information is available on the chronic consequences of radial artery removal for coronary artery bypass surgery on forearm circulation. Author Affiliation: (a) Departments of Cardiac Surgery and Angiology, Rome, Italy (b) Catholic University, Rome, Italy. Article History: Received 18 October 2004; Revised 18 January 2005; Accepted 10 February 2005 more...

The AID/APOBEC polynucleotide cytidine deaminases have historically been classified as either DNA mutators or RNA editors based on their first identified nucleic acid substrate preference. DNA mutators can generate functional diversity at antibody genes but also cause genomic instability in cancer. RNA editors can generate informational diversity in the transcriptome of innate immune cells, and of cancer cells. Members of both classes can act as antiviral restriction factors. Recent structural work has illuminated differences and similarities between AID/APOBEC enzymes that can catalyse DNA mutation, RNA editing or both, suggesting that the strict functional classification of members of this family should be reconsidered. As many of these enzymes have been employed for targeted genome (or transcriptome) editing, a more holistic understanding will help improve the design of therapeutically relevant programmable base editors. more...

IMPORTANCE: Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head. OBJECTIVE: To compare reported measures of efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of EczemA Trials database, and trial registries were searched through June 15, 2021. STUDY SELECTION: Randomized clinical trials examining 8 or more weeks of treatment with systemic immunomodulatory medications for moderate-to-severe atopic dermatitis were included after screening titles, abstracts, and papers in duplicate. DATA EXTRACTION AND SYNTHESIS: Data were abstracted in duplicate. Bayesian network meta-analyses and assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed. The updated analysis was completed from June to December 2021. MAIN OUTCOMES AND MEASURES: Outcomes include change in Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS). RESULTS: Since October 2019, 21 new studies were added, for a total of 60 trials with 16 579 patients. Up to 16 weeks of treatment in adults, abrocitinib, 200 mg daily (mean difference [MD], 2.2; 95% credible interval [CrI], 0.2-4.0; high certainty) and upadacitinib, 30 mg daily (MD, 2.7; 95% CrI, 0.6-4.7; high certainty) were associated with reduced EASI slightly more than dupilumab, 600 mg then 300 mg every 2 weeks. Abrocitinib, 100 mg daily (MD, −2.1; 95% CrI, −4.1 to −0.3; high certainty), baricitinib, 4 mg daily (MD, −3.2; 95% CrI, −5.7 to −0.8; high certainty), baricitinib, 2 mg daily (MD, −5.2; 95% CrI, −7.5 to −2.9; high certainty) and tralokinumab, 600 mg then 300 mg every 2 weeks (MD, −3.5; 95% CrI, −5.8 to −1.3; high certainty) were associated with reduced EASI slightly less than dupilumab. There was little or no difference between upadacitinib, 15 mg daily, and dupilumab (MD, 0.2; 95% CrI, −1.9 to 2.2; high certainty). The pattern of results was similar for POEM, DLQI, and PP-NRS. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, abrocitinib, 200 mg; and upadacitinib, 30 mg daily, were associated with slightly better scores than dupilumab, and upadacitinib, 15 mg daily, was associated with similar scores to dupilumab. Abrocitinib, 100 mg daily, baricitinib, 4 mg and 2 mg daily, and tralokinumab, 300 mg, every 2 weeks were associated with slightly worse scores. more...

Analysis of the SARS-CoV-2 transcriptome has revealed a background of low-frequency intra-host genetic changes with a strong bias towards transitions. A similar pattern is also observed when inter-host variability is considered. We and others have shown that the cellular RNA editing machinery based on ADAR and APOBEC host-deaminases could be involved in the onset of SARS-CoV-2 genetic variability. Our hypothesis is based both on similarities with other known forms of viral genome editing and on the excess of transition changes, which is difficult to explain with errors during viral replication. Zong et al. criticize our analysis on both conceptual and technical grounds. While ultimate proof of an involvement of host deaminases in viral RNA editing will depend on experimental validation, here, we address the criticism to suggest that viral RNA editing is the most reasonable explanation for the observed intra- and inter-host variability. more...

Histone deacetylase 4 (HDAC4) is a stress‐responsive factor that mediates multiple cellular responses. As a member of class IIa HDACs, HDAC4 shuttles between the nucleus and the cytoplasm; however, HDAC4 cytoplasmic functions have never been fully investigated. Duchenne muscular dystrophy (DMD) is a genetic, progressive, incurable disorder, characterized by muscle wasting, which can be treated with the unspecific inhibition of HDACs, despite this approach being only partially effective. More efficient strategies may be proposed for DMD only after the different HDAC members will be characterized. To fully understand HDAC4 functions, we generated dystrophic mice carrying a skeletal muscle‐specific deletion of HDAC4 (mdx;KO mice). The progression of muscular dystrophy was characterized in mdx and age‐matched mdx;KO mice by means of histological, molecular, and functional analyses. Satellite cells (SCs) from these mice were differentiated in vitro, to identify HDAC4 intrinsic functions influencing the myogenic potential of dystrophic SCs. Gain‐of‐function experiments revealed the cytoplasmic functions of HDAC4 in mdx;KO muscles. Histone deacetylase 4 increased in the skeletal muscles of mdx mice (~3‐fold; P< 0.05) and of DMD patients (n= 3, males, mean age 13.3 ± 1.5 years), suggesting that HDAC4 has a role in DMD. Its deletion in skeletal muscles importantly worsens the pathological features of DMD, leading to greater muscle fragility and degeneration over time. Additionally, it impairs SC survival, myogenic potential, and muscle regeneration, ultimately compromising muscle function (P< 0.05–0.001). The impaired membrane repair mechanism in muscles and SCs accounts for the mdx;KO phenotype. Indeed, the ectopic expression of Trim72, a major player in the membrane repair mechanism, prevents SC death (~20%; P< 0.01) and increases myogenic fusion (~40%; P< 0.01) in vitro; in vivoit significantly reduces myofibre damage (~10%; P< 0.005) and improves mdx;KO muscle function (P< 0.05). The mdx;KO phenotype is also fully rescued by restoring cytoplasmic levels of HDAC4, both in vitroand in vivo. The protective role of HDAC4 in the cytoplasm of mdx;KO muscles is, in part, independent of its deacetylase activity. HDAC4 expression correlates with Trim72 mRNA levels; furthermore, Trim72 mRNA decays more rapidly (P< 0.01) in mdx;KO muscle cells, compared with mdx ones. Histone deacetylase 4 performs crucial functions in the cytoplasm of dystrophic muscles, by mediating the muscle repair response to damage, an important role in ensuring muscle homeostasis, probably by stabilizing Trim72 mRNA. Consequently, the cytoplasmic functions of HDAC4 should be stimulated rather than inhibited in muscular dystrophy treatments, a fact to be considered in future therapeutic approaches. more...

The discovery of new original scaffolds for selective RNA targeting is one of the main challenges of current medicinal chemistry since therapeutically relevant RNAs represent potential targets for a number of pathologies. Recent efforts have been devoted to the search for RNA ligands targeting the biogenesis of oncogenic miRNAs whose overexpression has been directly linked to the development of various cancers. In this work, we developed a new series of RNA ligands for the targeting of oncogenic miRNA biogenesis based on the 2-deoxystreptamine scaffold. The latter is part of the aminoglycoside neomycin and is known to play an essential role in the RNA interaction of this class of RNA binders. 2-deoxystreptamine was thus conjugated to natural and artificial nucleobases to obtain new binders of the oncogenic miR-372 precursor (pre-miR-372). We identified some conjugates exhibiting a similar biological activity to previously synthesized neomycin analogs and studied their mode of binding with the target pre-miR-372. more...

Introduction: The aim of the narrative review was to analyse the applications of nuclear medicine (NM) techniques such as PET/CT with different tracers in combination with radiotherapy for the clinical management of glioblastoma patients. Materials and methods: Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. Results: This paper contains a narrative report and a critical discussion of NM approaches in combination with radiotherapy in glioma patients. Conclusions: NM can provide the Radiation Oncologist several aids that can be useful in the clinical management of glioblastoma patients. At the same, these results need to be validated in prospective and multicenter trials. more...

The outstanding mechanical performances of two-dimensional (2D) materials make them appealing for the emerging fields of flextronics and straintronics. However, their manufacturing and integration in 2D crystal-based devices rely on a thorough knowledge of their hardness, elasticity, and interface mechanics. Here, we investigate the elasticity of highly strained monolayer-thick MoS2membranes, in the shape of micrometer-sized domes, by atomic force microscopy (AFM)-based nanoindentation experiments. A dome’s crushing procedure is performed to induce a local re-adhesion of the dome’s membrane to the bulk substrate under the AFM tip’s load. It is worth noting that no breakage, damage, or variation in size and shape are recorded in 95% of the crushed domes upon unloading. Furthermore, such a procedure paves the way to address quantitatively the extent of the van der Waals interlayer interaction and adhesion of MoS2by studying pull-in instabilities and hysteresis of the loading–unloading cycles. The fundamental role and advantage of using a superimposed dome’s constraint are also discussed. more...

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2006.02.033 Byline: Angelo Di Giorgio, Carlo Luigi Cardini, Paolo Sammartino, Simone Sibio, Enzo Naticchioni Author Affiliation: Dipartimento di Chirurgia 'Pietro Valdoni,' Universita degli Studi di Roma 'La Sapienza,' Rome, Italy Article History: Received 18 January 2006; Accepted 13 February 2006 more...

Peritoneal dissemination from colorectal cancer (CRC) has long been associated with unfavorable prognosis. However, in the last decades, the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was able to obtain up to 30% 5-year survival rate in selected centers. Despite the wide diffusion of CRS and HIPEC, until now, there are no clear recommendations on the drug of choice for HIPEC nor its technique, and safety and efficacy data of HIPEC regimens and techniques are lacking. We performed a retrospective analysis of a prospectively maintained database of 26 CRS and mitomycin C HIPEC with CO2recirculation (HIPEC-CO2) for CRC peritoneal metastasis (PM) performed at our center. The main endpoints were morbidity, mortality, the temperature of perfusate during HIPEC and metabolic changes throughout the procedure. Morbidity was assessed by analysis of postoperative adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Continuous variables of Arterial Blood Gas (ABG) analysis at three time-points were compared by the Student ttest. There were no postoperative deaths. The overall grade 3–4 CTCAE complications rate at 30 days was 38.4%, with ten severe adverse events occurring to six (23.0%) patients. The temperature within HIPEC perfusion maintained between 41 and 42 °C in all cases and we experienced no HIPEC-related intraoperative complications. We observed a significant difference between all baseline and pre-HIPEC ABG parameters evaluated but no statistically significant differences between pre- and post-HIPEC ABG outcomes. This study shows that mitomycin C HIPEC-CO2is feasible and has a safety profile comparable to that of other HIPEC techniques reported in the literature. Further research is needed to validate prospectively the safety and efficacy of this technique. more...

The architectural perfection and multivalency of dendrimers have made them useful for biodelivery via peripheral functionalization and the adjustment of dendrimer generations. Modulation of the core-forming and internal matrix-forming structures offers virtually unlimited opportunities for further optimization, but only in a few cases this has been made compatible with strict diastereomeric purity over molecularly diverse series, low toxicity, and limited synthetic effort. Fully regular star polymers built on biocompatible macrocyclic platforms, such as hyperbranched cyclodextrins, offer advantages in terms of facile synthesis and flexible compositions, but core elaboration in terms of shape and function becomes problematic. Here we report the synthesis and characterization of star polymers consisting of functional trehalose-based macrocyclic cores (cyclotrehalans, CTs) and aminothiourea dendron arms, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, display no cytotoxicity, and efficiently complex and deliver plasmid DNA in vitro and in vivo. When compared with some commercial cationic dendrimers or polymers, the new CT-scaffolded star polymers show better transfection efficiencies in several cell lines and structure-dependent cell selectivity patterns. Notably, the CT core could be predefined to exert Zn(II) complexing or molecular inclusion capabilities, which has been exploited to synergistically boost cell transfection by orders of magnitude and modulate the organ tropism in vivo. more...