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Abstract Background Although neuroimaging investigations have consistently demonstrated that “hyperresponsive” and “hyperconnected” visual cortices may represent the functional substrate of cortical spreading depolarization in patients with migraine with aura, the mechanisms which underpin the brain “tendency” to ignite the cortical spreading depolarization and, consequently, aura phenomenon are still matter of debate. Considering that triggers able to induce aura phenomenon constrain brain to increase global (such as physical activity, stressors and sleep abnormalities) or local (such as bright light visual stimulations) energy demand, a vascular supply unable to satisfy the increased energy requirement could be hypothesized in these patients. Methods Twenty-three patients with migraine with aura, 25 patients with migraine without aura and 20 healthy controls underwent a 3-Tesla MRI study. Cerebral blood flow and local functional connectivity (regional homogeneity) maps were obtained and registered to the MNI space where 100 cortical regions were derived using a functional local-global normative parcellation. A surrogate estimate of the regional neurovascular coupling for each subject was obtained at each parcel from the correlation coefficient between the z-scored ReHo map and the z-scored cerebral blood flow maps. Results A significantly higher regional cerebral blood flow across the visual cortex of both hemispheres (i.e. fusiform and lingual gyri) was detected in migraine with aura patients when compared to patients with migraine without aura (p

Abstract Segmentation of multiple sclerosis (MS) lesions on brain MRI scans is crucial for diagnosis, disease and treatment monitoring but is a time-consuming task. Despite several automated algorithms have been proposed, there is still no consensus on the most effective method. Here, we applied a consensus-based framework to improve lesion segmentation on T1-weighted and FLAIR scans. The framework is designed to combine publicly available state-of-the-art deep learning models, by running multiple segmentation tasks before merging the outputs of each algorithm. To assess the effectiveness of the approach, we applied it to MRI datasets from two different centers, including a private and a public dataset, with 131 and 30 MS patients respectively, with manually segmented lesion masks available. No further training was performed for any of the included algorithms. Overlap and detection scores were improved, with Dice increasing by 4-8% and precision by 3-4% respectively for the private and public dataset. High agreement was obtained between estimated and true lesion load (ρ = 0.92 and ρ = 0.97) and count (ρ = 0.83 and ρ = 0.94). Overall, this framework ensures accurate and reliable results, exploiting complementary features and overcoming some of the limitations of individual algorithms.

Abstract Superconducting microstrip single photon detectors (SMSPDs) are increasingly attracting the interest of the scientific community as a new platform for large area detectors with unprecedented advantaged in terms of fabrication. However, while their operativity at the telecommunication wavelength was achieved, working beyond 1.55 µm is challenging. Here, we experimentally demonstrate single-photon operation of NbRe microstrips at wavelengths of 1.55 and 2 µm. The devices are structured as pairs of parallel microstrips with widths ranging from 1.4 to 2.2 μm and lengths from 5 to 10 μm. This innovative design may assure large sensitive areas, without affecting the kinetic inductance, namely the time performance of the detectors. The results are discussed in the framework of the hot-spot two-temperature model.

Abstract Herein, additive manufacturing, which is extremely promising in different sectors, has been adopted in the electrical energy storage field to fabricate efficient materials for supercapacitor applications. In particular, Al2O3-, steel-, and Cu-based microparticles have been used for the realization of 3D self-assembling materials covered with reduced graphene oxide to be processed through additive manufacturing. Functionalization of the particles with amino groups and a subsequent "self-assembly" step with graphene oxide, which was contextually partially reduced to rGO, was carried out. To further improve the electrical conductivity and AM processability, the composites were coated with a polyaniline-dodecylbenzene sulfonic acid complex and further blended with PLA. Afterward, they were extruded in the form of filaments, printed through the fused deposition modeling technique, and assembled into symmetrical solid-state devices. Electrochemical tests showed a maximum mass capacitance of 163 F/g, a maximum energy density of 15 Wh/Kg at 10 A/g, as well as good durability (85% capacitance retention within 5000 cycles) proving the effectiveness of the preparation and the efficiency of the as-manufactured composites.

Introduction The TriAD study will assess the Xpert MTB/XDR (Xpert XDR; Cepheid) assay to detect tuberculosis (TB) drug resistance in sputum testing positive for TB to rapidly triage and treat patients with a short all-oral treatment regimen.Methods and analysis In this study, approximately 4800 Xpert MTB/RIF or Ultra MTB-positive patients (irrespective of rifampicin (RIF) resistance (RR) status) from several clinical sites across South Africa, Nigeria and Ethiopia will be enrolled over 18–24 months and followed-up for approximately 6 months post-TB treatment completion. Participants will be enrolled into one of two cohorts based on Xpert MTB/RIF and Xpert XDR results: Mycobacterium tuberculosis (M.tb) positive participants with RR in Cohort 1 (n=880) and M.tb positive RIF susceptible TB patients with isoniazid mono-resistance irrespective of presence of resistance to fluoroquinolones, second-line injectable drugs or ethionamide in Cohort 2 (n=400). Cohort 1 will be compared with historical cohorts from each implementing sites. The primary study outcomes include time to initiation of an appropriate treatment regimen by resistance profile and the proportion of patients with favourable treatment outcomes compared with historical cohorts from each of the implementing sites. Secondary outcomes include feasibility, acceptability and cost-effectiveness of this approach to inform policies and guidelines for programmatic implementation of this triage and treat model for drug-resistant tuberculosis management. Utility of the tuberculosis molecular bacterial load assay (TB-MBLA) for real-time treatment response assessment will also be evaluated.Ethics and dissemination The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and local research committees have provided ethical review and approval (BREC/00002654/2021, HREC 210805, NHREC/01/01/2007 and EPHI-IRB-459–2022). The South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval for the TRiAD Study (SAHPRA MD20211001). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.Trial registration number Clinicaltrials.gov; Trial registration number: NCT05175794; South African National Clinical Trials Register (SANCTR DOH-27-012022-4720)

Purpose: The correlates of complementary and alternative medicine (CAM) utilization among elders have not been fully investigated. This study was designed to identify such correlates in a large sample of older adults, thus generating new data relevant to consumer education, medical training, and health practice and policy. Design and Methods: A sub-sample from the 2000 Wave of the Health and Retirement Study (n=1,099) aged 52 or older were surveyed regarding use of CAM (chiropractic, alternative practitioners, dietary and herbal supplements, and personal practices). Results: Of respondents over 65 years of age, 88% used CAM, with dietary supplements and chiropractic most commonly reported (65% and 46%, respectively). Users of alternate practitioners and dietary supplements reported having more out-of-pocket expenses on health than nonusers of these modalities. Age correlated positively with use of dietary supplements and personal practices and inversely with alternative practitioner use. Men reported less CAM use than women, except for chiropractic and personal practices. Blacks and Hispanics used fewer dietary supplements and less chiropractic, but they reported more personal practices than Whites. Advanced education correlated with fewer chiropractic visits and more dietary and herbal supplement and personal practices use. Higher income, functional impairment, alcohol use, and frequent physician visits correlated with more alternative practitioner use. There was no association between CAM and number of chronic diseases. Implications: The magnitude and patterns of CAM use among elders lend considerable importance to this field in public health policy making and suggest a need for further epidemiological research and ongoing awareness efforts for both patients and providers.

Abstract Some previous observations suggest that a low platelet count is associated with an increased risk of adverse outcomes in patients with acute coronary syndromes (ACS). However, most of the data come from post-hoc analyses of randomized controlled trials and from studies including thrombocytopenia developed during hospital stay. Our aim was to assess the impact of low platelet count at admission on cardiovascular outcomes and treatment approach in patients hospitalized for ACS in a current real-life setting in Italy. Patients admitted to Italian coronary care units for ACS were enrolled in the START-ANTIPLATELET registry. Baseline clinical characteristics and treatment at discharge were recorded. Patients were followed-up at 6 months, 1 year and yearly thereafter. Low platelet count was defined as a count at admission 100 k/µl or 100 k/µl and 30 (1.6%) 100 k/µl: 37.6 vs 41.8 months, p = 0.002; HR = 2.7, 95% CIs 1.4–5.2;

Abstract Background Over the last two decades, tumor-derived RNA expression signatures have been developed for the two most commonly diagnosed tumors worldwide, namely prostate and breast tumors, in order to improve both outcome prediction and treatment decision-making. In this context, molecular signatures gained by main components of the tumor microenvironment, such as cancer-associated fibroblasts (CAFs), have been explored as prognostic and therapeutic tools. Nevertheless, a deeper understanding of the significance of CAFs-related gene signatures in breast and prostate cancers still remains to be disclosed. Methods RNA sequencing technology (RNA-seq) was employed to profile and compare the transcriptome of CAFs isolated from patients affected by breast and prostate tumors. The differentially expressed genes (DEGs) characterizing breast and prostate CAFs were intersected with data from public datasets derived from bulk RNA-seq profiles of breast and prostate tumor patients. Pathway enrichment analyses allowed us to appreciate the biological significance of the DEGs. K-means clustering was applied to construct CAFs-related gene signatures specific for breast and prostate cancer and to stratify independent cohorts of patients into high and low gene expression clusters. Kaplan-Meier survival curves and log-rank tests were employed to predict differences in the outcome parameters of the clusters of patients. Decision-tree analysis was used to validate the clustering results and boosting calculations were then employed to improve the results obtained by the decision-tree algorithm. Results Data obtained in breast CAFs allowed us to assess a signature that includes 8 genes (ITGA11, THBS1, FN1, EMP1, ITGA2, FYN, SPP1, and EMP2) belonging to pro-metastatic signaling routes, such as the focal adhesion pathway. Survival analyses indicated that the cluster of breast cancer patients showing a high expression of the aforementioned genes displays worse clinical outcomes. Next, we identified a prostate CAFs-related signature that includes 11 genes (IL13RA2, GDF7, IL33, CXCL1, TNFRSF19, CXCL6, LIFR, CXCL5, IL7, TSLP, and TNFSF15) associated with immune responses. A low expression of these genes was predictive of poor survival rates in prostate cancer patients. The results obtained were significantly validated through a two-step approach, based on unsupervised (clustering) and supervised (classification) learning techniques, showing a high prediction accuracy (≥ 90%) in independent RNA-seq cohorts. Conclusion We identified a huge heterogeneity in the transcriptional profile of CAFs derived from breast and prostate tumors. Of note, the two novel CAFs-related gene signatures might be considered as reliable prognostic indicators and valuable biomarkers for a better management of breast and prostate cancer patients.

Abstract Background Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the onset of puberty or the susceptibility to a wide range of diseases later in life. The present study aims to investigate changes in genomic DNA methylation profiles associated with pubertal onset analyzing human peripheral blood leukocytes from three different groups of subjects: 19 girls with central precocious puberty (CPP), 14 healthy prepubertal girls matched by age and 13 healthy pubertal girls matched by pubertal stage. For this purpose, the comparisons were performed between pre- and pubertal controls to identify changes in normal pubertal transition and CPP versus pre- and pubertal controls. Results Analysis of methylation changes associated with normal pubertal transition identified 1006 differentially methylated CpG sites, 86% of them were found to be hypermethylated in prepubertal controls. Some of these CpG sites reside in genes associated with the age of menarche or transcription factors involved in the process of pubertal development. Analysis of methylome profiles in CPP patients showed 65% and 55% hypomethylated CpG sites compared with prepubertal and pubertal controls, respectively. In addition, interestingly, our results revealed the presence of 43 differentially methylated genes coding for zinc finger (ZNF) proteins. Gene ontology and IPA analysis performed in the three groups studied revealed significant enrichment of them in some pathways related to neuronal communication (semaphorin and gustation pathways), estrogens action, some cancers (particularly breast and ovarian) or metabolism (particularly sirtuin). Conclusions The different methylation profiles of girls with normal and precocious puberty indicate that regulation of the pubertal process in humans is associated with specific epigenetic changes. Differentially methylated genes include ZNF genes that may play a role in developmental control. In addition, our data highlight changes in the methylation status of genes involved in signaling pathways that determine the migration and function of GnRH neurons and the onset of metabolic and neoplastic diseases that may be associated with CPP in later life.

Abstract Background Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce. Aims We investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity. Methods We performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded. Results Both TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels (p = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased (p = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient (p = 0.007) while in TDT no correlation was found. Conclusion Relative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment.

Abstract Background Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. Due to its favorable safety profile, E4 was recently approved as estrogenic component of a new combined oral contraceptive. E4 is a selective ligand of estrogen receptor (ER)α and ERβ, but its binding to the G Protein-Coupled Estrogen Receptor (GPER) has not been described to date. Therefore, we aimed to explore E4 action in GPER-positive Triple-Negative Breast Cancer (TNBC) cells. Methods The potential interaction between E4 and GPER was investigated by molecular modeling and binding assays. The whole transcriptomic modulation triggered by E4 in TNBC cells via GPER was explored through high-throughput RNA sequencing analyses. Gene and protein expression evaluations as well as migration and invasion assays allowed us to explore the involvement of the GPER-mediated induction of the plasminogen activator inhibitor type 2 (SERPINB2) in the biological responses triggered by E4 in TNBC cells. Furthermore, bioinformatics analysis was aimed at recognizing the biological significance of SERPINB2 in ER-negative breast cancer patients. Results After the molecular characterization of the E4 binding capacity to GPER, RNA-seq analysis revealed that the plasminogen activator inhibitor type 2 (SERPINB2) is one of the most up-regulated genes by E4 in a GPER-dependent manner. Worthy, we demonstrated that the GPER-mediated increase of SERPINB2 is engaged in the anti-migratory and anti-invasive effects elicited by E4 in TNBC cells. In accordance with these findings, a correlation between SERPINB2 levels and a good clinical outcome was found in ER-negative breast cancer patients. Conclusions Overall, our results provide new insights into the mechanisms through which E4 can halt migratory and invasive features of TNBC cells.

A 71-year-old woman was admitted to the hospital after consuming food due to acute malnutrition and abdominal pain. Reduced patency of all jejunoileal branches and the superior mesenteric artery was observed in the abdominal computed tomography scan. Abdominal angina was caused by atherosclerosis, the frequent use of triptans for recurrent migraines, the JAK2 mutation, and a high platelet count. The patient’s complete parenteral nutrition was not spared, despite the development of a collateral circulation preventing fatal acute ischemia.

Abstract Detection of subjects with oral potentially malignant disorders in a population is key to early detection of oral cancer (OC) with consequent reduction of cancer-related morbidity and mortality. Our aim was to investigate the prevalence and associated risk factors for OPMD in representative provinces of Indonesia. This cross-sectional study was undertaken in five Indonesian provinces: West Java (WJ), Jakarta (JKT), West Papua (WP), West Kalimantan (WK) and Banda Aceh (BA). Respondents answered a previously validated questionnaire including information on ethnicity, occupation, socioeconomic status (SES), oral health practices, and behaviours associated with oral cancer. An oral examination was undertaken using WHO standardized methodology. Data were analysed using ANOVA, Chi-Square, and logistic regression to assess association between risk factors and mucosal disease. A total of 973 respondents between the ages of 17 and 82 years was enrolled (WJ 35.5%,JKT 13.3% WP 18.3%, WK 9%, BA 23.9%). Tobacco smoking (14.8%), Betel quid (BQ) chewing (12.6%) and alcohol drinking (4%) varied geographically. A well-established OPMD was detected in 137 (14.1%) respondents and 2 (0.2%) presented with chronic ulceration later diagnosed as OC. Leukoplakia was the most common OPMD found (9.7%), while the prevalence of oral submucous fibrosis (OSMF), not previously described in the nation, was 2.3%. Poor knowledge of OC risk factors, poor oral hygiene behaviours, low-income SES and ethnicity were significantly associated with the presence of an OPMD. There is a previously under-reported high prevalence of OPMD in Indonesia. Overall, we found a strong correlation between the presence of an OPMD and individual habituation to known risk factors.

Abstract In the present paper, multifunctional flower-like nanoparticles were synthesized to be used in the leather finishing. They are capable of conferring simultaneously and synergistic antimicrobial, self-cleaning, light resistance, hydrophobic, mechanical, thermal, and fluorescent properties due to the presence of Ag, TiO2, and SiO2 NPs. These nanoparticles form a “flower-like” structure in which the “pistil” is made up of TiO2 and the “petals” that surround it of silver nanoparticles and silica nanoparticles, whose dimensions are of the order of ten nanometers. Their surfaces enjoy abundant hydrophilic functionalities to be dispersed within inks commonly used during the leather finishing process. Leathers functionalized with these nanomaterials showed significantly improved self-cleaning properties after 15 h of exposure to UV light, and antibacterial properties 10 times higher than that shown by the untreated samples. Aging tests were performed (ISO 105-B02, ISO 17228, SAEJ 2412). ΔE, color variation decreased by approximately 30%, if compared with samples not refined with flower-like NPs. Furthermore, the results of the mechanical tests (ISO 17076, FCA 50444) evidence amazing properties, e.g. abrasion resistance more than significantly improved, increase in resistance from 1500 cycles for the untreated samples to 3000 cycles for the leathers finished with flower-like NPs. The contact angle analysis, capturing the angle that traces the air–water to water–substrate interface from the origin of the air–water-substrate contact point at the edge, is practically unchanged after 10 s in the case of nanoparticles containing finishing.

Introduction Sexually transmitted diseases (STDs) are a major cause of long-term disability. Urethral discharge syndrome (UDS), abnormal vaginal discharge (AVD) and genital ulcer disease (GUD) are very common in low-income and middle-income countries (LMICs), where, due to lack of resources, these infections are managed according to a syndromic approach. Although microbiological diagnosis using nuclear acid amplification tests (NAAT) is already a standard to prescribe targeted treatments in industrialised countries, no randomised clinical trials have been conducted to evaluate clinical usefulness and acceptability of NAAT in comparison with syndromic approach in LMICs. The results of this study could inform diagnostic guidelines since they may suggest an update of the current recommendation if microbiological diagnosis using NAAT in the management of STD is demonstrated to be both useful and acceptable in an LMIC context.Methods and analysis The primary objective of this randomised, open-label trial is to evaluate the clinical usefulness of a NAAT and its acceptability in comparison with a clinical syndromic approach and to explore whether this test could replace the syndromic approach in the management of STDs at a national referral hospital in Uganda. 220 patients presenting to the STD clinic at Mulago Hospital in Kampala, Uganda with AVD, UDS or GUD will be randomised to either standard of care (syndromic management) or NAAT-based treatment with a 1:1 ratio. All the patients will be asked to return after 2 or 3 weeks for a control visit. Primary outcome will be therapeutic appropriateness.Ethics and dissemination This trial was approved by the Mulago Hospital Research and Ethical Committee (MHREC2023-97) and the Uganda National Council for Science and Technology (HS31000ES). Patients will give informed consent to participate before taking part in the study. Results will be published in peer-reviewed journals in open-access formats and data made available in anonymised form.Trial registration number NCT05994495.

Introduction Physical restraint (PR) is prescribed in patients receiving invasive mechanical ventilation in the intensive care unit (ICU) to avoid unplanned removal of medical devices. However, it is associated with an increased risk of delirium. We hypothesise that a restrictive use of PR, as compared with a systematic use, could reduce the duration of delirium in ICU patients receiving invasive mechanical ventilation.Methods and analysis The Restrictive use of Restraints and Delirium Duration in ICU (R2D2-ICU) study is a national multicentric, parallel-group, randomised (1:1) open-label, controlled, superiority trial, which will be conducted in 10 ICUs. A total of 422 adult patients requiring invasive mechanical ventilation for an expected duration of at least 48 hours and eligible for prescription of PR will be randomly allocated within 6 hours from intubation to either the restrictive PR use group or the systematic PR use group, until day 14, ICU discharge or death, whichever comes first. In both groups, PR will consist of the use of wrist straps. The primary endpoint will be delirium or coma-free days, defined as the number of days spent alive in the ICU without coma or delirium within the first 14 days after randomisation. Delirium will be assessed using the Confusion Assessment Method-ICU twice daily. Key secondary endpoints will encompass agitation episodes, opioid, propofol, benzodiazepine and antipsychotic drug exposure during the 14-day intervention period, along with a core outcome set of measures evaluated 90 days postrandomisation.Ethics and dissemination The R2D2-ICU study has been approved by the Comité de Protection des Personnes (CPP) ILE DE FRANCE III—PARIS (CPP19.09.06.37521) on June 10th, 2019). Participant recruitment started on 25 January 2021. Results will be published in international peer-reviewed medical journals and presented at conferences.Trial registration number NCT04273360.

Abstract In the accompanying study, Nimmo and colleagues estimated the dates of emergence of mutations in mmpR5 (Rv0678), the most important resistance gene to the anti-tuberculosis drug bedaquiline, in over 3500 geographically diverse Mycobacterium tuberculosis genomes. This provided important insights to improve the design and analysis of clinical trials, as well as the World Health Organization catalogue of resistance mutations, the global reference for interpreting genotypic antimicrobial susceptibility testing results.

The exposome encompasses all endogenous and exogenous exposure individuals encounter throughout their lives, including biological, chemical, physical, psychological, relational, and socioeconomic factors. It examines the duration and intensity of these types of exposure and their complex interactions over time. This interdisciplinary approach involves various scientific disciplines, particularly toxicology, to understand the long-term effects of toxic exposure on health. Factors like air pollution, racial background, and socioeconomic status significantly contribute to diseases such as metabolic, cardiovascular, neurodegenerative diseases, infertility, and cancer. Advanced analytical methods measure contaminants in biofluids, food, air, water, and soil, but often overlook the cumulative risk of multiple chemicals. An exposome analysis necessitates sophisticated tools and methodologies to understand health interactions and integrate findings into precision medicine for better disease diagnosis and treatment. Chronic exposure to environmental and biological stimuli can lead to persistent low-grade inflammation, which is a key factor in chronic non-communicable diseases (NCDs), such as obesity, cardiometabolic disorders, cancer, respiratory diseases, autoimmune conditions, and depression. These NCDs are influenced by smoking, unhealthy diets, physical inactivity, and alcohol abuse, all shaped by genetic, environmental, and social factors. Dietary patterns, especially ultra-processed foods, can exacerbate inflammation and alter gut microbiota. This study investigates the exposome’s role in the prevention, development, and progression of NCDs, focusing on endogenous and exogenous factors.

Abstract An early and accurate detection of different subtypes of tumors is crucial for an effective guidance to personalized therapy and in predicting the ability of tumor to metastasize. Here we exploit the Surface Enhanced Raman Scattering (SERS) platform, based on disordered silver coated silicon nanowires (Ag/SiNWs), to efficiently discriminate genomic DNA of different subtypes of melanoma and colon tumors. The diagnostic information is obtained by performing label free Raman maps of the dried drops of DNA solutions onto the Ag/NWs mat and leveraging the classification ability of learning models to reveal the specific and distinct physico-chemical interaction of tumor DNA molecules with the Ag/NW, here supposed to be partly caused by a different DNA methylation degree.

Abstract Cangrelor, the first intravenous P2Y12 inhibitor (P2Y12-I), has been approved on the basis of three large RCTs from the CHAMPION program which nevertheless have been criticized for the low bleeding risk of the enrolled patients, the large quote of chronic coronary syndromes, and the use of Clopidogrel as control arm even in the setting of acute coronary syndromes (ACS). We sought to investigate, in the setting of ACS, the comparative performance of Cangrelor in terms of in-hospital ischemic and haemorrhagic outcomes compared with the current gold-standard of oral P2Y12-I. The study retrospectively enrolled 686 consecutive patients admitted to the Divisions of Cardiology of Policlinico of Bari and L. Bonomo Hospital of Andria for ACS and treated with percutaneous coronary intervention. The study population was divided according to the P2Y12-I treatment strategy in two groups: patients given an oral P2Y12-I and patients receiving Cangrelor in the cath lab followed by an oral P2Y12-I. Clinical endpoints included death, ischemic and bleeding events occurring during hospital stay. Cangrelor treated patients presented higher clinical risk profile at presentation and faced higher death rate. However, after PS matching, in-hospital mortality resulted comparable between the groups and Cangrelor use was associated with reduced in-hospital definite stent thrombosis (p = 0.03). Data from our real-world registry highlight that, in the setting of ACS, Cangrelor is prevalently used in patients with very challenging clinical presentations. The adjusted analysis provides for the first time promising data on stent thrombosis reduction associated with Cangrelor use.

Abstract Background The gold standard anesthesiologic procedure for urgent femur fracture surgery is Spinal Anesthesia. It is not always feasible because of patients' severe comorbidities and difficulties in optimizing drug therapy in the appropriate time frame such as discontinuation of anticoagulant drugs. The use of four peripheral nerve blocks (tetra-block) can be a winning weapon when all seems lost. Case presentation We present, in this case series, three Caucasian adult femur fractures (an 83-year-old woman, a 73-year-old man, and a 68-year-old woman) with different and major comorbidities (cardiac or circulatory disorders on anticoagulants therapy that were not discontinued on time; breast cancer and others) underwent the same anesthesiologic approach in the urgent setting. Ultrasound peripheral nerve blocks, that is femoral, lateral femoral cutaneous, obturator, and sciatic with parasacral approach were successfully performed in all patients who underwent intramedullary nailing for intertrochanteric fracture. We evaluated the adequacy of the anesthesia plane, postoperative pain control with the VAS scale, and the incidence of postoperative side effects. Conclusions Four peripheral nerve blocks (Tetra-block) can be alternative anesthesiologic management in urgent settings, in patients where drug therapy cannot be optimized, as in antiplatelet and anticoagulant therapy.

Abstract Introduction Advanced neuroimaging techniques have extensively contributed to elucidate the complex mechanisms underpinning the pathophysiology of migraine, a neurovascular disorder characterized by episodes of headache associated with a constellation of non-pain symptoms. The present manuscript, summarizing the most recent progresses of the arterial spin labelling (ASL) MRI techniques and the most significant findings from ASL studies conducted in migraine, is aimed to clarify how ASL investigations are contributing to the evolving insight on migraine pathophysiology and their putative role in migraine clinical setting. ASL techniques, allowing to quantitatively demonstrate changes in cerebral blood flow (CBF) both during the attacks and in the course of interictal period, could represent the melting point between advanced neuroimaging investigations, conducted with pure scientific purposes, and conventional neuroimaging approaches, employed in the diagnostic decision-making processes. Main body Converging ASL evidences have demonstrated that abnormal CBF, exceeding the boundaries of a single vascular territory, with biphasic trend dominated by an initial hypoperfusion (during the aura phenomenon but also in the first part of the headache phase) followed by hyperperfusion, characterizes migraine with aura attack and can represent a valuable clinical tool in the differential diagnosis from acute ischemic strokes and epileptic seizures. Studies conducted during migraine without aura attacks are converging to highlight the involvement of dorsolateral pons and hypothalamus in migraine pathophysiology, albeit not able to disentangle their role as “migraine generators” from mere attack epiphenomenon. Furthermore, ASL findings tend to support the presence of perfusion abnormalities in brain regions known to be involved in aura ignition and propagation as well as in areas involved in multisensory processing, in both patients with migraine with aura and migraine without aura. Conclusion Although ASL studies have dramatically clarified quality and timing of perfusion abnormalities during migraine with aura attacks, the same cannot be said for perfusion changes during migraine attacks without aura and interictal periods. Future studies with more rigorous methodological approaches in terms of study protocol, ASL technique and sample selection and size are mandatory to exploit the possibility of better understanding migraine pathophysiology and identifying neuroimaging biomarkers of each migraine phase in different migraine phenotypes.

Abstract Background Migraine affects 1.1 billion people globally and is the second leading cause of disability worldwide. In clinical trials, treatment efficacy is evaluated by comparing the differential responses in the treatment and placebo arms. Although placebo response in preventive migraine trials has been studied, there is limited research examining temporal trends. This study evaluates the trend of placebo response over thirty years in migraine prevention trials and investigates the association of potential confounders, such as patient, treatment, and study characteristics on placebo response using meta-analysis with regression. Methods We conducted literature searches from January 1990 to August 2021 in bibliographical databases (PubMed, Cochrane Library, and EMBASE). Studies were selected according to PICOS criteria and included randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adult patients diagnosed with episodic or chronic migraine, with or without aura. The protocol was registered with PROSPERO (CRD42021271732). Migraine efficacy outcomes included were either continuous (e.g., monthly migraine days) or dichotomous (e.g., ≥ 50% responder rate (yes/no)). We assessed the correlation of the change in outcome from baseline in the placebo arm, with the year of publication. The relationship between placebo response and year of publication was also assessed after accounting to confounders. Results A total of 907 studies were identified, and 83 were found eligible. For the continuous outcomes, the change from baseline in mean placebo response showed an increase over the years (rho = 0.32, p = 0.006). The multivariable regression analysis also showed an overall increase in placebo response over the years. The correlation analysis of dichotomous responses showed no significant linear trend between publication year and mean placebo response (rho = 0.08, p = 0.596). Placebo response also varied by route of administration. Conclusion Placebo response increased over the past 30 years in migraine preventive trials. This phenomenon should be considered when designing clinical trials and conducting meta-analyses.

Study Design Case-control study. Purpose Analyze association between imaging factors related to the failure of conservative treatment in isolated subaxial cervical facet fractures. Overview of Literature Facet fracture (F1, F2, and F3 AOSpine) may be stable or unstable depending on clinical and imaging variables, which are not well established. As a result, differences in fracture management lead to differences in surgical or conservative indications, and there is no evidence to predict conservative treatment failure. Methods Patients were categorized into two groups: six patients (16.2%) with conservative treatment failure (defined as the appearance of neurological symptoms, listhesis >3.5 mm, kyphotic deformation >11°, and/or non-union), and 31 patients (83.7%) with successful conservative management (defined as complete consolidation confirmed by computed tomography [CT] at the 6-month follow-up). All participants were fitted with rigid collars of the Miami type, and standardized follow-up was performed until consolidation or failure. CT and magnetic resonance imaging (MRI) was used to examine imaging characteristics. Sagittal balance parameters were assessed using CT, and signs of acute disc injury, prevertebral edema, facet synovitis, and interspinous hyperintense signal were assessed using MRI. Results Thirty-seven patients were diagnosed with unilateral cervical facet fractures between 2009 and 2020. In this sample, acute disc injury had a significative association to failure of conservative treatment in F2 and F3 AOSpine facet fractures, 100% of the failure group presented with traumatic disc injury compared to 9.7% of the successful group, for the other variables: prevertebral edema, 83.7% vs. 41.9%; facet synovitis, 100% vs. 77.4%; and interspinous hyperintensity, 71.4% vs. 38.7%, respectively. With conservative management, all F1 fractures healed successfully. Conservative treatment failed in 20% of F2 fractures and 50% of F3 fractures, respectively. In terms of cervical sagittal balance parameters, there were no significant differences between groups. Conclusions Conservative management was successful in all F1 fractures. In F2 and F3 types, there was a significant association between acute disc injury and conservative treatment failure.

Abstract Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disease characterized by near complete absence of functional adipose tissue from birth. CGL diagnosis can be based on clinical data including acromegaloid features, acanthosis nigricans, reduction of total body fat, muscular hypertrophy, and protrusion of the umbilical scar. The identification and knowledge of CGL by the health care professionals is crucial once it is associated with severe and precocious cardiometabolic complications and poor outcome. Image processing by deep learning algorithms have been implemented in medicine and the application into routine clinical practice is feasible. Therefore, the aim of this study was to identify congenital generalized lipodystrophy phenotype using deep learning. A deep learning approach model using convolutional neural network was presented as a detailed experiment with evaluation steps undertaken to test the effectiveness. These experiments were based on CGL patient’s photography database. The dataset consists of two main categories (training and testing) and three subcategories containing photos of patients with CGL, individuals with malnutrition and eutrophic individuals with athletic build. A total of 337 images of individuals of different ages, children and adults were carefully chosen from internet open access database and photographic records of stored images of medical records of a reference center for inherited lipodystrophies. For validation, the dataset was partitioned into four parts, keeping the same proportion of the three subcategories in each part. The fourfold cross-validation technique was applied, using 75% (3 parts) of the data as training and 25% (1 part) as a test. Following the technique, four tests were performed, changing the parts that were used as training and testing until each part was used exactly once as validation data. As a result, a mean accuracy, sensitivity, and specificity were obtained with values of [90.85 ± 2.20%], [90.63 ± 3.53%] and [91.41 ± 1.10%], respectively. In conclusion, this study presented for the first time a deep learning model able to identify congenital generalized lipodystrophy phenotype with excellent accuracy, sensitivity and specificity, possibly being a strategic tool for detecting this disease.

Abstract Oral and intestinal mucositis are debilitating inflammatory diseases observed in cancer patients undergoing chemo-radiotherapy. These are devastating clinical conditions which often lead to treatment disruption affecting underlying malignancy management. Although alimentary tract mucositis involves the entire gastrointestinal tract, oral and intestinal mucositis are often studied independently utilizing distinct organ-specific pre-clinical models. This approach has however hindered the development of potentially effective whole-patient treatment strategies. We now characterize a murine model of alimentary tract mucositis using 5-Fluorouracil (5-FU). Mice were given 5-FU intravenously (50 mg/kg) or saline every 48 h for 2 weeks. Post initial injection, mice were monitored clinically for weight loss and diarrhea. The incidence and extent of oral mucositis was assessed macroscopically. Microscopical and histomorphometric analyses of the tongue and intestinal tissues were conducted at 3 interim time points during the experimental period. Repeated 5-FU treatment caused severe oral and intestinal atrophy, including morphological damage, accompanied by body weight loss and mild to moderate diarrhea in up to 77.8% of mice. Oral mucositis was clinically evident throughout the observation period in 88.98% of mice. Toluidine blue staining of the tongue revealed that the ulcer size peaked at day-14. In summary, we have developed a model reproducing the clinical and histologic features of both oral and intestinal mucositis, which may represent a useful in vivo pre-clinical model for the study of chemotherapy-induced alimentary tract mucositis and the development of preventative therapies.

Volleyball performance depends partially on lower limb strength. The phase angle (PhA) is a marker of functional muscle mass and a surrogate measure of athletic muscle performance. This study aimed to verify the correlation between PhA (bioimpedance) and lower limb muscle strength in young volleyball athletes. The sample included 38 young male volleyball athletes (Age: 16.7±1.3 years; Weight: 73.7±9.7 kg; Height: 179.3±6.9 cm). We performed a cross-sectional observational study and evaluated the volleyball athletes for vertical jump tests (Counter-Movement Jump: CMJ and Squat Jump: SJ) and whole-body bioimpedance. The Pearson test showed positive and moderate significant correlations between the PhA, CMJ, and SJ (r=0.550 and r=0.559, respectively). Our findings demonstrated that assessing the PhA through bioimpedance provides relevant measures of muscle strength and power in young volleyball athletes.

Abstract The deformation style of the continental lithosphere is a relevant issue for geodynamics and seismic hazard perspectives. Here we show the first evidence of two well-distinct low-angle and SW-dipping individual reverse shear zones of the Italian Outer Thrust System in Central Italy. One corresponds to the down-dip prosecution of the Adriatic Basal Thrust with its major splay and the other to a hidden independent structure, illuminated at a depth between 25 and 60 km, for an along-strike extent of ~ 150 km. Combining geological information with high-quality seismological data, we unveil this novel configuration and reconstruct a detailed 3D geometric and kinematic fault model of the compressional system, active at upper crust to upper mantle depths. In addition, we report evidence of coexisting deformation volumes undergoing well-distinguished stress fields at different lithospheric depths. These results provide fundamental constraints for a forthcoming discussion on the Apennine fold-and-thrust system's geodynamic context as a shallow subduction zone or an intra-continental lithosphere shear zone.

Abstract The present retrospective study included both intrauterine insemination and in vitro assisted reproductive technologies (ART) procedures performed from January 2009 to December 2018 at a tertiary-care Fertility Centre. The purpose was to assess the incidence of ectopic pregnancy (EP) in infertile population who undergoes ART and to identify any risk factor impacting the occurrence of EP after ART. Among 27,376 cycles, 7352 pregnancies were achieved, of which 132 were EPs, the 1.80% (95% CI 1.5–2.1) of all pregnancies. In fresh embryo transfer cycles, a history of prior pelvic adhesions showed the greatest impact on the incidence of EP (aOR 2.49 95% CI 1.53–4.07 p

A bioimpedância fornece dados do ângulo de fase, sendo utilizado para monitorar atletas. A força e a potência musculares são características fisiológicas/motoras importantes nos esportes que envolvem movimentos intensos. O objetivo deste estudo foi verificar relações entre a composição corporal, o ângulo de fase e a força de membros superiores/inferiores em atletas adolescentes de diferentes esportes. A amostra foi constituída por 473 atletas (Masculino: 285 e Feminino: 188), com idade média de 16,4+1,2 anos. A estatística adotada foi Análise das Componentes Principais, com grupos de análise formados como Geral, Masculino e Feminino. Os testes de Kaiser-Meyer-Olkin e Bartlett´s (p

Abstract Pediatric osteomyelitis is an insidious disease that can lead to permanent sequelae, the management of which still relies on lengthy intravenous antibiotic therapy. The purpose of this study is to report and describe the clinical course and outcome of pediatric bacterial osteomyelitis in our experience. We reported the clinical, diagnostic, and treatment characteristics of all cases of osteomyelitis in children younger than 18 years of age who were hospitalized between January 2010 and December 2021 at the Bambino Gesù Children’s Hospital in Rome, Italy, we compared patients with and without complications at follow-up, to identify any predictive factor for sequelae. The study sample included 319 cases of pediatric bacterial osteomyelitis. The median age was 7.77 years. Males (60.8%) were more affected than females. The most affected bones were the femur, tibia, and spine. Etiology was identified in 40.1% of cases, with S.aureus as the most common causative agent. Sequelae were reported in 43 cases (13.5%). The main predictors of sequelae were sepsis on admission and hypergammaglobulinemia. Our results show that a severe presentation with sepsis and hypergammaglobulinemia on admission may be associated with a higher frequency of late sequelae. Early recognition and aggressive treatment of this subgroup of patients may lead to a reduction in complications.

Introduction: The transmission of drug-resistant tuberculosis is one of the greatest challenges facing the global tuberculosis control.Aim: The aim of the study was to investigate the resent transmission of rifampicin resistant tuberculosis in Bulgaria and to describe the mutations related to the antimicrobials’ resistance using whole genome sequencing.Materials and methods: As part of an ECDC funded pilot study for evaluation of the systematic use of whole genome sequencing (WGS) of Mycobacterium tuberculosis (MTB) surveillance (EUSeqMyTB), Bulgaria provided 65 rifampicin resistant isolates over a three years’ timeframe (2017-2019) representing 87.5% of the notified rifampicin resistant cases. Drug resistance prediction and relatedness analysis of the resistant isolates was performed in collaboration with San Raffaele Scientific Institute, Milan, Italy.Results: Almost all of the isolates were identified as Euro-American lineage (96.9%); 18.5% of the isolates were found to be resistant to fluoroquinolones, but no mutations conferring resistance to bedaquiline or linezolid could be identified. Less than half (43.3%) of the isolates were clustered (

Football is a sport that involves a combination of continuous and intermittent effort. Therefore, players need to be able to recover quickly between moments of high intensity to continue to perform at a high level of output throughout the entire match. The present study aimed to evaluate the effect of an intermittent exercise protocol on the rate of high-intensive force production through the countermovement test (CMJ) in elite Portuguese female soccer players. The sample consisted of 12 players from the first division of women's football in Portugal (Age = 18.1 ± 0.9 years; Weight = 60.10 ± 5.8 Kg; Height = 1.63 ± 4.8 cm; BMI = 22.48 ± 1.5 kg/m2). The players performed an intermittent exercise protocol on a cycle ergometer, lasting 8 minutes, in which each minute corresponded to 40 seconds of high-intensity (4W/kg, based on the player's body weight) and 20 seconds of low-intensity (75W). Before and after the protocol, the players performed the CMJ. Through the results obtained, it was possible to observe that players presented a significant decrease in the height of the CMJ between the two moments (before- 29.92 ± 3.55cm vs after- 26.92 ± 4.05cm; p < 0.01). The present study allowed us to conclude that intermittent exercise protocol promoted a negative influence on CMJ performance.

An otherwise healthy 32-year-old woman suffered from finger ischemia. An echocardiogram and CT scan revealed a mobile mass in the left ventricle that was attached to the anterior papillary muscle and did not involve the valve leaflets. The tumor was resected and histopathology confirmed it to be a papillary fibroelastoma. Our case emphasizes the significance of a comprehensive diagnostic workup for a peripheral ischemic lesion. This resulted in the discovery of an unusual intra-ventricular origin for a commonly benign tumor.

Abstract Studying faults capable of releasing moderate-to-strong earthquakes is fundamental for seismic hazard studies, especially in a territory that was subject to the strongest peninsular Italy earthquake (1857, Mw 7.1) and hosting the largest European oil field on-land. Fieldwork-based observations in the Campania-Lucania area highlight a SSW-dipping ~ 65 km-long normal-oblique-segmented fault, showing evidence of recent activity and possibly responsible for the 1857 earthquake. It crosses the Maddalena ridge, linking separate Quaternary basins. Two seismic reflection profiles cross the fault trace where it is buried beneath the Val d’Agri Quaternary deposits. Similarities between fault-controlled small basins in the highest portion of the massifs in the study area and the neighboring 1980 Irpinia area (1980 earthquake, Mw 6.9) are interpreted as evidence of trans-ridge fault activity. Kinematic analyses and the stress field inversion provide a N032-trending near-horizontal s3-axis, the same computed in literature for the Irpinia area, highlighting a deviation from the ~N045-axis which characterizes most of the Apennines. This study demonstrates how detailed fieldwork, supported by geophysics and innovative data analysis techniques, can unravel unknown faults while giving a novel interpretation of the trans-ridge faults' style in controlling strong earthquakes, moving away from classical interpretations, and providing a helpful approach in similar contexts worldwide.

Abstract Background Metabolic disorders are associated with increased incidence, aggressive phenotype and poor outcome of breast cancer (BC) patients. For instance, hyperinsulinemia is an independent risk factor for BC and the insulin/insulin receptor (IR) axis is involved in BC growth and metastasis. Of note, the anti-diabetic metformin may be considered in comprehensive therapeutic approaches in BC on the basis of its antiproliferative effects obtained in diverse pre-clinical and clinical studies. Methods Bioinformatics analysis were performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project. The naturally immortalized BC cell line, named BCAHC-1, as well as cancer-associated fibroblasts (CAFs) derived from BC patients were used as model systems. In order to identify further mechanisms that characterize the anticancer action of metformin in BC, we performed gene expression and promoter studies as well as western blotting experiments. Moreover, cell cycle analysis, colony and spheroid formation, actin cytoskeleton reorganization, cell migration and matrigel drops evasion assays were carried out to provide novel insights on the anticancer properties of metformin. Results We first assessed that elevated expression and activation of IR correlate with a worse prognostic outcome in estrogen receptor (ER)-positive BC. Thereafter, we established that metformin inhibits the insulin/IR-mediated activation of transduction pathways, gene changes and proliferative responses in BCAHC-1 cells. Then, we found that metformin interferes with the insulin-induced expression of the metastatic gene CXC chemokine receptor 4 (CXCR4), which we found to be associated with poor disease-free survival in BC patients exhibiting high levels of IR. Next, we ascertained that metformin prevents a motile phenotype of BCAHC-1 cells triggered by the paracrine liaison between tumor cells and CAFs upon insulin activated CXCL12/CXCR4 axis. Conclusions Our findings provide novel mechanistic insights regarding the anti-proliferative and anti-migratory effects of metformin in both BC cells and important components of the tumor microenvironment like CAFs. Further investigations are warranted to corroborate the anticancer action of metformin on the tumor mass toward the assessment of more comprehensive strategies halting BC progression, in particular in patients exhibiting metabolic disorders and altered insulin/IR functions.

Abstract Background The continuous emergence of SARS-CoV-2 variants of concern (VOC) with immune escape properties, such as Delta (B.1.617.2) and Omicron (B.1.1.529), questions the extent of the antibody-mediated protection against the virus. Here we investigated the long-term antibody persistence in previously infected subjects and the extent of the antibody-mediated protection against B.1, B.1.617.2 and BA.1 variants in unvaccinated subjects previously infected, vaccinated naïve and vaccinated previously infected subjects. Methods Blood samples collected 15 months post-infection from unvaccinated (n=35) and vaccinated (n=41) previously infected subjects (Vo’ cohort) were tested for the presence of antibodies against the SARS-CoV-2 spike (S) and nucleocapsid (N) antigens using the Abbott, DiaSorin, and Roche immunoassays. The serum neutralising reactivity was assessed against B.1, B.1.617.2 (Delta), and BA.1 (Omicron) SARS-CoV-2 strains through micro-neutralisation. The antibody titres were compared to those from previous timepoints, performed at 2- and 9-months post-infection on the same individuals. Two groups of naïve subjects were used as controls, one from the same cohort (unvaccinated n=29 and vaccinated n=20) and a group of vaccinated naïve healthcare workers (n=61). Results We report on the results of the third serosurvey run in the Vo’ cohort. With respect to the 9-month time point, antibodies against the S antigen significantly decreased (P=0.0063) among unvaccinated subjects and increased (P

Abstract The emergence and spread of resistant tuberculosis (TB) pose a threat to public health, so it is necessary to diagnose the drug-resistant forms in a clinically short time frame and closely monitor their transmission. In this study, we carried out a first whole genome sequencing (WGS)-based analysis of multidrug resistant (MDR) M. tuberculosis strains to explore the phylogenetic lineages diversity, drug resistance mechanisms, and ongoing transmission chains within the country. In total, 65 isolates phenotypically resistant to at least rifampicin and isoniazid collected in the Czech Republic in 2005–2020 were enrolled for further analysis. The agreement of the results obtained by WGS with phenotypic drug susceptibility testing (pDST) in the determination of resistance to isoniazid, rifampicin, pyrazinamide, streptomycin, second-line injectables and fluoroquinolones was more than 80%. Phylogenetic analysis of WGS data revealed that the majority of MDR M. tuberculosis isolates were the Beijing lineage 2.2.1 (n = 46/65; 70.8%), while the remaining strains belonged to Euro-American lineage. Cluster analysis with a predefined cut-off distance of less than 12 single nucleotide polymorphisms between isolates showed 19 isolates in 6 clusters (clustering rate 29.2%), located mainly in the region of the capital city of Prague. This study highlights the utility of WGS as a high-resolution approach in the diagnosis, characterization of resistance patterns, and molecular-epidemiological analysis of resistant TB in the country.

Abstract Infectious and inflammatory stimuli elicit the generation of chitinase-3-like protein-1 (CHI3L1), involved in tissue damage, repair and remodeling. We evaluated whether plasma CHI3L1 at disease onset predicts clinical outcome of patients with Coronavirus 2019 (COVID-19) disease. Blood from 191 prospectively followed COVID-19 patients were collected at hospital admission between March 18th and May 5th, 2020. Plasma from 80 survivors was collected one month post-discharge. Forty age- and sex-matched healthy volunteers served as controls. Primary outcome was transfer to intensive care unit (ICU) or death. CHI3L1 was higher in COVID-19 patients than controls (p

Abstract The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including

Arecoline is the primary active carcinogen found in areca nut and has been implicated in the pathogenesis of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). For this study, we conducted a stepwise review process by combining iterative scoping reviews with a post hoc search, with the aim of identifying the specific mechanisms by which arecoline initiates and promotes oral carcinogenesis. Our initial search allowed us to define the current trends and patterns in the pathophysiology of arecoline-induced OSF and OSCC, which include the induction of cell proliferation, facilitation of invasion, adhesion, and migration, increased collagen deposition and fibrosis, imbalance in immune and inflammatory mechanisms, and genotoxicity. Key molecular pathways comprise the activation of NOTCH1, MYC, PRDX2, WNT, CYR61, EGFR/Pl3K, DDR1 signaling, and cytokine upregulation. Despite providing a comprehensive overview of potential pathogenic mechanisms of OSF, the involvement of molecules functioning as areca alkaloid receptors, namely, the muscarinic and nicotinic acetylcholine receptors (AChRs), was not elucidated with this approach. Accordingly, our search strategy was refined to reflect these evidence gaps. The results of the second round of reviews with the post hoc search highlighted that arecoline binds preferentially to muscarinic AChRs, which have been implicated in cancer. Consistently, AChRs activate the signaling pathways that partially overlap with those described in the context of arecoline-induced carcinogenesis. In summary, we used a theory-driven interpretive review methodology to inform, extend, and supplement the conventional systematic literature assessment workflow. On the one hand, the results of this critical interpretive synthesis highlighted the prevailing trends and enabled the consolidation of data pertaining to the molecular mechanisms involved in arecoline-induced carcinogenesis, and, on the other, brought up knowledge gaps related to the role of the local cholinergic axis in oral carcinogenesis, thus suggesting areas for further investigation.

Abstract Intrauterine growth restriction (IUGR) is associated with a higher incidence of perinatal complications as well as cardiovascular and renal diseases later on. A better insight into the disease mechanisms underlying these sequalae is important in order to identify which IUGR infants are at a higher risk and find strategies to improve their outcome. In this prospective case–control study we examined whether IUGR had any effect on renal and cerebral perfusion and oxygen saturation in term neonates. We integrated near-infrared spectroscopy (NIRS), echocardiographic, Doppler and renal function data of 105 IUGR infants and 105 age/gender-matched controls. Cerebral and renal regional oxygen saturation values were measured by NIRS during the first 12 h after birth. Echocardiography alongside Doppler assessment of renal and anterior cerebral arteries were performed at 6, 24, 48 and 72 h of age. Glomerular and tubular functions were also assessed. We found a left ventricular dysfunction together with a higher cerebral oxygen saturation and perfusion values in the IUGR group. IUGR term infants showed a higher renal oxygen saturation and a reduced oxygen extraction together with a subclinical renal damage, as indicated by higher values of urinary neutrophil gelatinase-associated lipocalin and microalbumin. These data suggest that some of the haemodynamic changes present in growth-restricted foetuses may persist postnatally. The increased cerebral oxygenation may suggest an impaired transition to normal autoregulation as a consequence of intra-uterine chronic hypoxia. The higher renal oxygenation may reflect a reduced renal oxygen consumption due to a subclinical kidney damage.

Abstract NbRe-based superconducting thin films recently received relevant interest in the field of low-temperature electronics. However, for these materials the electrical conduction mechanisms, in particular in the normal state, still need to be investigated in more detail. Here, NbRe and NbReN films of different thicknesses have been deposited on two different substrates, namely monocrystalline Si and $$\text {SiO}_2$$ SiO 2 buffered Si. The films were characterized by DC electrical transport measurements. Moreover, a connection with the charge carriers fluctuation processes has been made by analyzing the electrical noise generated in the normal state region. Despite the films morphology seems not to be affected by the substrate used, a lower noise level has been found for the ones grown on $$\text {SiO}_2$$ SiO 2 , in particular for NbReN. From this study it emerges that both NbRe and NbReN ultrathin films are of very good quality, as far as the low-temperature electrical noise and conduction are concerned, with noise levels competitive with NbN. These results may further support the proposal of using these materials in a nanowire form in the field of superconducting electronics.

Non-small cell lung cancer (NSCLC) represents 85% of all new lung cancer diagnoses and presents a high recurrence rate after surgery. Thus, an accurate prediction of recurrence risk in NSCLC patients at diagnosis could be essential to designate risk patients to more aggressive medical treatments. In this manuscript, we apply a transfer learning approach to predict recurrence in NSCLC patients, exploiting only data acquired during its screening phase. Particularly, we used a public radiogenomic dataset of NSCLC patients having a primary tumor CT image and clinical information. Starting from the CT slice containing the tumor with maximum area, we considered three different dilatation sizes to identify three Regions of Interest (ROIs): CROP (without dilation), CROP 10 and CROP 20. Then, from each ROI, we extracted radiomic features by means of different pre-trained CNNs. The latter have been combined with clinical information; thus, we trained a Support Vector Machine classifier to predict the NSCLC recurrence. The classification performances of the devised models were finally evaluated on both the hold-out training and hold-out test sets, in which the original sample has been previously divided. The experimental results showed that the model obtained analyzing CROP 20 images, which are the ROIs containing more peritumoral area, achieved the best performances on both the hold-out training set, with an AUC of 0.73, an Accuracy of 0.61, a Sensitivity of 0.63, and a Specificity of 0.60, and on the hold-out test set, with an AUC value of 0.83, an Accuracy value of 0.79, a Sensitivity value of 0.80, and a Specificity value of 0.78. The proposed model represents a promising procedure for early predicting recurrence risk in NSCLC patients.

Abstract Background Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. Patients and methods Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The “Paediatric Bleeding Questionnaire Scoring Key” was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. Results Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03). Conclusions Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

Objectives The aim of this study was to investigate the relationship of echocardiographic parameters, laboratory findings and clinical characteristics with in-hospital mortality in adult patients with COVID-19 admitted to the intensive care units (ICU) in two large collaborating tertiary UK centres.Design Observational retrospective study.Setting The study was conducted in patients admitted to the ICU in two large tertiary centres in London, UK.Participants Inclusion criteria were: (1) patients admitted to the ICU with a COVID-19 diagnosis over a period of 16 weeks. and (2) underwent a transthoracic echocardiogram on the first day of ICU admission as clinically indicated.No exclusion criteria applied.Three hundred patients were enrolled and completed the follow-up.Primary and secondary outcome measures The outcome measure in this study was in-hospital mortality in patients admitted to the ICU with COVID-19 infection.Results Older age (HR: 1.027, 95% CI 1.007 to 1.047; p=0.008), left ventricular (LV) ejection fraction 0.7).Conclusions In patients with COVID-19 in the ICU, both severely impaired LV function and impaired RV function may have adverse prognostic implications, but older age and inflammatory markers appear to have a greater impact. A combination of echocardiographic and laboratory investigations as well as demographic and clinical characteristics appears appropriate for risk stratification in patients with COVID-19 who are admitted to the ICU.

We have developed an inducible Huntington’s disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (~50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow-up revealed that the benefits, in all mHtt-lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12 months of age, and late mHtt lowering did not ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefits in humans.