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Vaginal breech delivery (VBD) has been widely discouraged over the last two decades due to associated neonatal risks. However, many gynaecologists are still challenging this approach, at least in selected settings.To study short-term neonatal outcomes in singleton pregnancies undergoing VBD.Retrospective cohort study conducted on singleton pregnancies who delivered in breech presentation between 2012 and 2019. Neonatal complications in terms of mortality, umbilical artery (UA) pH, 5-min Apgar score, and postnatal admission to neonatal intensive care unit (NICU) were evaluated.Overall, 804 breech deliveries were considered. Of these, 53.86 % had VBD, 26.62 % had emergency caesarean sections (CS) and 19.53 % had elective CS. No perinatal deaths were reported. After multivariate adjustment, VBD was associated with higher incidence of UA pH 7.10 compared with both elective and emergency CS. No significant associations were found between VBD and UA pH 7.00 or 5-min Apgar score 3 or 7. No significant differences in NICU hospitalization were observed for different modes of delivery. Gestational age was inversely correlated with UA pH 7.00, 5-min Apgar score 3 and 7, and NICU hospitalization.VBD in an experienced setting does not increase the risk of negative short-term perinatal outcomes significantly. Gestational age was the most important risk factor for low UA pH or 5-min Apgar score and NICU hospitalization, independent of mode of delivery.

Bullous pemphigoid is the most common autoimmune bullous dermatosis. In recent years several studies have tried to identify the main factors of the disease related with an increased risk of death. The aim of this multicenter Italian study was to assess the risk score of death considering epidemiologic, clinical, immunological, and therapeutic factors in a cohort of patients affected by bullous pemphigoid and try to identify the cumulative survival up to 120 months.We retrospectively reviewed the medical records of patients with bullous pemphigoid who were diagnosed between 2005 and 2020 in the 12 Italian centers. Data collected included sex, age at the time of diagnosis, laboratory findings, severity of disease, time at death/censoring, treatment, and multimorbidity.A total of 572 patients were included in the study. The crude mortality rate was 20.6%, with an incidence mortality rate of 5.9 × 100 person/year. The mortality rate at 1, 3, 5, and 10 years was 3.2%, 18.2%, 27.4% and 51.9%, respectively. Multivariate model results showed that the risk of death was significantly higher in patients older than 78 years, in presence of multimorbidity, anti-BP180 autoantibodies72 U/mL, or anti-BP230 3 U/mL at diagnosis. The variables jointly included provided an accuracy (Harrel's Index) of 77% for predicting mortality.This study represents the first nationwide Italian study to have retrospectively investigated the mortality rates and prognostic factors in patients with bullous pemphigoid. A novel finding emerged in our study is that a risk prediction rule based on simple risk factors (age, multimorbidity, steroid-sparing drugs, prednisone use, and disease severity) jointly considered with two biomarkers routinely measured in clinical practice (anti-BP230 and anti-BP180 autoantibodies) provided about 80% accuracy for predicting mortality in large series of patients with this disease.

Uric acid is the final product of purine metabolism, and its increased serum levels have been directly involved in the pathogenesis and natural history of hypertension. The relationship between elevated uric acid and hypertension has been proven in both animals and humans, and its relevance is already evident in childhood and adolescent population. The mechanism responsible for blood pressure increase in hyperuricemic subjects is implicating both oxidative stress and intracellular urate activity with a primary involvement of XOR (xanthine-oxidoreductase activity). An increase in the relative risk of hypertension has been confirmed by genetic data and by large meta-analyses of epidemiological data. The effects of urate-lowering treatment on blood pressure control in patients with elevated serum uric acid has been investigated in a small number of reliable studies with a large heterogeneity of patient populations and study designs. However, 2 large meta-analyses suggest a significant effect of urate-lowering treatment on blood pressure, thus confirming the significant relationship between high serum urate and blood pressure. The future research should be focused on a more appropriate identification of patients with cardiovascular hyperuricemia by considering the correct cardiovascular threshold of serum urate, the time-course of uricemia fluctuations, and the identification of reliable markers of urate overproduction that could significantly clarify the clinical and therapeutic implications of the interaction between serum uric acid and hypertension.

TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures. In this report, we present the clinical and molecular features of seven previously unreported individuals, identified by exome sequencing, with the recurrent p.(Val837Met) variant and global developmental delay. Other shared clinical features included congenital hypotonia, dysmorphic facial features (broad forehead, deep-set eyes, and down turned mouth), exotropia, and musculoskeletal issues (hip dysplasia, hip dislocation, scoliosis). Seizures were observed in two of seven individuals (febrile seizure in one and generalized tonic–clonic seizures with atonic drops in another), and epileptiform activity was observed in an additional two individuals. This report extends the number of affected individuals to 16 who are heterozygous for the de novo recurrent substitution p.(Val837Met). In contrast with the initial report, epilepsy was not a mandatory feature observed in this series. TRPM3 pathogenic variation should be considered in individuals with global developmental delays, moderate–severe intellectual disability with, or without, childhood-onset epilepsy.

Atezolizumab in combination with nab-paclitaxel has been introduced for the treatment of locally advanced or recurrent triple negative breast cancer (TNBC). Patient selection relies on the use of immunohistochemistry using a specific monoclonal PD-L1 antibody (clone SP142) in a tightly controlled companion diagnostic test (CDx) with a defined interpretative algorithm. Currently there are no standardized recommendations for selecting the optimal tissue to be tested and there is limited data to support decision making, raising the possibility that tissue selection may bias test results. We compared PD-L1 SP142 assessment in a collection of 73 TNBC cases with matched core biopsies and excision samples. There was good correlation between PD-L1-positive core biopsy and subsequent excision, but we found considerable discrepancy between PD-L1 negative core biopsy and matched excision, with a third of cases found negative on core biopsies converting to positive upon examination of the excision tissue. In view of these findings, we developed a workflow for the clinical testing of TNBC for PD-L1 and implemented it in a central referral laboratory. We present audit data from the clinical PD-L1 testing relating to 2 years of activities, indicating that implementation of this workflow results in positivity rates in our population of TNBC similar to those of IMpassion130 clinical trial. We also developed an online atlas with a precise numerical annotation to aid pathologists in the interpretation of PD-L1 scoring in TNBC.

Peter MA Calverley,1 Alberto Papi,2 Clive Page,3 Paola Rogliani,4 Roberto W Dal Negro,5 Mario Cazzola,4 Arrigo F Cicero,6 Jadwiga A Wedzicha7 1Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; 2Respiratory Medicine, University of Ferrara, Ferrara, Italy; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London, UK; 4Respiratory Medicine Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 5National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 6Medical and Surgical Department, University of Bologna, Bologna, Italy; 7Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: Peter MA Calverley, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK, Tel +44 1515295886, Fax +44 1515295888, Email pmacal@liverpool.ac.ukPurpose: To explore the effect of erdosteine on COPD exacerbations, health-related quality of life (HRQoL), and subjectively assessed COPD severity.Patients and methods: This post-hoc analysis of the RESTORE study included participants with COPD and spirometrically moderate (GOLD 2; post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted; n = 254), or severe airflow limitation (GOLD 3; post-bronchodilator FEV1 30‒49% predicted; n = 191) who received erdosteine 300 mg twice daily or placebo added to usual maintenance therapy for 12 months. Antibiotic and oral corticosteroid use was determined together with patient-reported HRQoL (St George’s Respiratory Questionnaire, SGRQ). Patient and physician subjective COPD severity scores (scale 0‒4) were rated at baseline, 6 and 12 months. Data were analyzed using descriptive statistics for exacerbation severity, COPD severity, and treatment group. Comparisons between treatment groups used Student’s t-tests or ANCOVA as appropriate.Results: Among GOLD 2 patients, 43 of 126 erdosteine-treated patients exacerbated (7 moderate-to-severe exacerbations), compared to 62 of 128 placebo-treated patients (14 moderate-to-severe exacerbations). Among those with moderate-to-severe exacerbations, erdosteine-treated patients had a shorter mean duration of corticosteroid treatment (11.4 days vs 13.3 days for placebo, P = 0.043), and fewer patients required antibiotic treatment with/without oral corticosteroids (71.4% vs 85.8% for placebo, P < 0.001). Erdosteine-treated GOLD 2 patients who exacerbated showed significant improvements from baseline in SGRQ total scores and subjective disease severity scores (patient- and physician-rated), compared with placebo-treated patients regardless of exacerbation severity. Among GOLD 3 patients, there were no significant differences between treatment groups on any of these measures.Conclusion: Adding erdosteine to the usual maintenance therapy of COPD patients with moderate airflow limitation reduced the number of exacerbations, the duration of treatment with corticosteroids and the episodes requiring treatment with antibiotics. Additionally, treatment with erdosteine improved HRQoL and patient-reported disease severity.Keywords: antibiotic, chronic obstructive pulmonary disease, erdosteine, COPD exacerbation, health-related quality of life, systemic corticosteroid

RAI1 is a dosage-sensitive gene whose decreased or increased expression by recurrent and non-recurrent 17p11.2 deletions or duplications causes Smith-Magenis (SMS) or Potocki-Lupski syndromes (PTLS), respectively. Here we report on a 21-year-old female patient showing SMS phenotype who was found to carry a 3.4 kb de novo intragenic RAI1 deletion. Interestingly, a significant increase in RAI1 transcript levels was identified in the patient’s, brother’s and mother’s peripheral blood cells. Allele-specific dosage analysis revealed that the patient’s maternally inherited overexpressed RAI1 allele harbors the intragenic deletion, confirming the SMS diagnosis due to the presence of a single wild-type RAI1 functional allele. The mother and brother do not present any PTLS neurologic/behavioral clinical features. Extensive sequencing of RAI1 promoter and predicted regulatory regions showed no potential causative variants accounting for gene overexpression. However, the mother and both children share a novel private missense variant in RAI1 exon 3, currently classified as a VUS (uncertain significance), though predicted by two bioinformatic tools to disrupt the binding site of one specific transcription factor. The reported familial case, the second showing RAI1 overexpression in the absence of RAI1 duplication, may help to understand the regulation of RAI1 dosage sensitivity although its phenotypic effect remains to be determined.

Objective: To estimate whether the topical debriding agent, Debrichem, could potentially afford the UK's National Health Service (NHS) a cost-effective intervention for the management of hard-to-heal venous leg ulcers (VLUs). Method: A Markov model was constructed depicting the management of hard-to-heal VLUs with Debrichem plus standard care (SC) or SC alone over a period of 12 months. The model was populated with inputs from an indirect comparison of two propensity score-matched cohorts. The model estimated the cost-effectiveness of the two interventions in terms of the incremental cost per quality–adjusted life year (QALY) gained at 2019/20 prices. Results: Addition of Debrichem to a SC protocol to treat hard-to-heal VLUs was found to increase the probability of healing by 75% (from 0.35 to 0.61) by 12 months, and to increase health-related quality of life over 12 months from 0.74 to 0.84 QALYs per patient. The 12-month cost of treatment with Debrichem plus SC (£3128 per patient) instead of SC alone (£7195 per patient) has the potential to reduce the total NHS cost of wound management by up to 57%. Hence, Debrichem was estimated to improve health outcomes for less cost. Sensitivity analysis showed that Debrichem plus SC remained a cost-effective (dominant) treatment with plausible variations in costs and effectiveness. Conclusion: Within the limitations of the study, the addition of Debrichem to a SC protocol potentially affords a cost-effective treatment to the NHS for managing hard-to-heal VLUs.

Lifestyle improvement is a cornerstone of cardiovascular disease prevention and has a relevant effect on blood pressure control. During the last decades the attention of the researcher has focused on low-salt diets as the lifestyle modification most effective in blood pressure reduction. Current international guidelines thus suggest to stress the importance of the implementation of the dietary approach to stop hypertension (DASH) diet and of a low-salt Mediterranean diet to achieve the best results in term of blood pressure decrease. However, salt reduction in diet could be not the only nor the main determinant of blood pressure reduction under dietary treatment. DASH and low-salt Mediterranean diet are also characterized by a high intake of vegetables (NO and polyphenol sources), whole grains, some low-fat dairy products, and low intake of red meat, sugar, and trans-hydrogenated fats. Lacto-ovo vegetarian diet are also per se associated to a significant improvement in blood pressure levels. Moreover, these diets are particularly effective when associated with a significant weight loss. Furthermore, blood pressure can also be lowered by some nutraceuticals (beetroot, magnesium, vitamin C, catechin-rich beverages, lycopene, etc). The aim of this narrative review is to critically resume the most recent evidence supporting a complete approach to dietary counseling for hypertension prevention and management.

Two score families were introduced to help clinicians about the decision-making regarding intracranial aneurysms management. The first family estimates the growth/rupture risk (GRS), whereas the second provides straightforward recommendation (RS) for treatment decisions. However, both remain poorly validated and little is known about their agreement. In this paper, we performed a retrospective concordance analysis among the two scores families through their application to a multicenter cohort of SAH patients.Demographical, clinical and radiological data were extracted in conformance with the variables included in PHASES, UCAS, ELAPSS, Juvela's growth score (JGS), UIATS and Juvela's treatment score (JTS). Individual patients' score were calculated for both score families, and pooled data were then analyzed.Overall, 146 patients were included. True positive rates were: 51.4% for PHASES; 71.9% for UCAS; between 60.3% and 90.4% for JTS; and between 27.4% and 68.5% for UIATS. In patients showing UIATS unclear recommendation and low JTS score (RS), UCAS outperformed PHASES (GRS) in identifying aneurysms at higher risk of rupture. Same results we found for patients with conservative UIATS recommendation and very low JTS score. Forty-to-sixty percent of aneurysms with unclear or conservative RS recommendation would have been identified as at high risk with GRS.Retrospectively applied, JTS appeared outperforming UIATS in correctly recommending treatment in a higher percentage of patients. UIATS and JTS appeared agreeing more with UCAS than PHASES predictions. Around 50% of patients with unclear or conservative UIATS/JTS recommendations were been classified as at higher growth risk by ELAPSS and JGS.

To analyze the retino-choroidal vascular characteristics of patients affected by pigmented paravenous chorio-retinal atrophy by means of optical coherence tomography (OCT) angiography.This study was designed as an observational, cross-sectional case series. Multimodal imaging included fundus autofluorescence, structural OCT, and OCT angiography. The quantitative OCT angiography analyses included the calculation of the vessel density and choriocapillaris porosity.Overall, 12 patients (24 eyes) affected by pigmented paravenous chorio-retinal atrophy were recruited. Structural OCT of the areas involved by pigmented paravenous chorio-retinal atrophy as visualized on the fundus autofluorescence showed a complete ellipsoid zone and external limiting membrane absence, with thinning of ganglion cell complex, outer nuclear layer, and outer plexiform layer, but associated with the optical partial preservation of the retinal pigment epithelium. Optical coherence tomography angiography quantitative assessment of the retinal regions affected by PPRCA, as visualized by fundus autofluorescence, was characterized by normal vessel density at the level of superficial capillary plexus but significantly altered vessel density of deep capillary plexus and choriocapillaris, with higher choriocapillaris porosity. The presence of macular atrophy was significantly correlated with worse deep capillary plexus and choriocapillaris vessel density values. Furthermore, a statistically significant correlation between the fundus autofluorescence patterns and the retinal vascular status was found.Optical coherence tomography angiography quantitative analyses in pigmented paravenous chorio-retinal atrophy demonstrate a specific impairment at the level of the deep capillary plexus, which could in turn bring about a thinning of ganglion cell complex and outer nuclear layer. The alterations at the level of the choriocapillaris and the choroid, in general, could then represent a secondary effect.

Whether tumor suppressor candidate 2 (TUSC2) plays an important role in glioblastoma (GBM) progression is largely unknown. Whether TUSC2 undergoes polyubiquitination is unknown. Herein, we report that TUSC2 protein expression is reduced/lost in GBM compared to normal brain due to protein destabilization; TUSC2 mRNA is equally expressed in both tissues. NEDD4 E3 ubiquitin ligase polyubiquitinates TUSC2 at residue K71, and the TUSC2-K71R mutant is resistant to NEDD4-mediated proteasomal degradation. Analysis of GBM specimens showed NEDD4 protein is highly expressed in GBM and the level is inversely correlated with TUSC2 protein levels. Furthermore, TUSC2 restoration induces apoptosis and inhibits patient-derived glioma stem cells (PD-GSCs) in vitro and in vivo. Conversely, TUSC2-knockout promotes PD-GSCs in vitro and in vivo. RNA-Seq analysis and subsequent validations showed GBM cells with TUSC2- knockout expressed increased Bcl-xL and were more resistant to apoptosis induced by a Bcl-xL-specific BH3 mimetic. A TUSC2- knockout gene signature created from the RNA-seq data predicts poor patient survival. Together, these findings establish that NEDD4-mediated polyubiquitination is a novel mechanism for TUSC2 degradation in GBM and that TUSC2 loss promotes GBM progression in part through Bcl-xL upregulation.

Background and aim: General population awareness about cardiovascular risk factors is usually low. The aim of the present study was to evaluate the vascular aging of subjects aware and not aware to be hypertensive, hypercholesterolemic, hypertriglyceridemic or diabetics in a general population sample. Methods and results: We interviewed 1652 subjects without atherosclerotic cardiovascular diseases (M: 46.6%, F: 53.4%) about their awareness of hypertension, hypercholesterolemia, hypertriglyceridemia or type 2 diabetes. Then we compared the augmentation index and pulse wave velocity of subjects aware and not aware of the investigated cardiovascular risk factors. 1049 participants declared not to be hypertensive, while 32 were not sure. Among them, respectively, 23.5% and 50% were hypertensive. Subjects not aware of their hypertension had significantly higher aortic blood pressure than aware ones (p < 0.001). 841 participants declared not to be hypercholesterolemic, while 60 were not sure. Among them, respectively, 18.1% and 40% were hypercholesterolemic. Subjects not aware of their hypercholesterolemia had significantly higher augmentation index than the aware ones (p < 0.05). 1226 participants declared not to be hypertriglyceridemic, while 200 were not sure. Among them, respectively, 19.2% and 44% were hypertriglyceridemic. Subjects not aware of their hypertriglyceridemia had significantly higher TG levels aware ones (p < 0.05), although this seemed to not related to increased arterial stiffness. 1472 participants declared not to be diabetic, while 20 were not sure. Among them, respectively, 2.0% and 25.0% were diabetics. Subjects not aware of their diabetes had significantly higher augmentation index than the aware ones (p < 0.05). Conclusions: In conclusion, the lack of awareness of hypertension and hypercholesterolemia is relatively frequent in the general population and is associated to significantly higher arterial stiffness.

Background FKBP51 immunophilin is abundantly expressed by immune cells. Co-inhibitory immune receptor signalling generates the splicing isoform FKBP51s. Tregs stained by FKBP51s are increased in melanoma patients and their counts are associated with anti-CTLA-4 response. An expansion of FKBP51s+PD-L1+ monocytes was measured in a group of non-responding patients to anti-CTLA-4. The aim of this work was to confirm the predictive value of response of FKBP51s+Tregs in a cohort of patients undergoing anti-PD1 treatment and shed light on a monocyte subset co-expressing PD-L1/FKBP51s. Methods Co-cultures of organoids and autologous lymphocytes were used to confirm that tumour T-cell interaction can induce FKBP51s. PBMC immunophenotype and flow cytometry served to assess and monitor FKBP51s+Treg and FKBP51s+PD-L1+ monocytes in 22 advanced melanoma patients treated with anti-PD1. Silencing and overexpression of FKBP51s in human macrophages served to address the protein role in the tolerant macrophages’ behaviour. Results FKBP51s+Tregs count was increased in responders and had a prognostic value. Non-responders showed an early increase in FKBP51s+ PD-L1+ monocytes during anti-PD1 treatment. Manipulation of FKBP51s modulated the macrophage–phenotype, with forced protein expression promoting aspects associated with tolerance. Conclusions FKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy. Manipulation of FKBP51s may overcome resistance.

Introduction: The present study aimed at evaluating Italian epidemiological trends of pediatric inflammatory bowel diseases (IBD) over the period 2009–2018. Materials and methods: Data from 1969 patients enrolled in the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition Registry, by 49 pediatric IBD centers throughout the country, were analyzed, comparing three different time intervals (2009–2012, 2013–2015, 2016–2018). Results: The number of new IBD diagnoses ranged from 175 to 219 per year, evenly distributed over the examined period of time. From 2009 to 2018, the minimal incidence ranged from 1.59 to 2.04 /105 inhabitants aged < 18 years, with an overall slight predominance of ulcerative colitis (UC) over Crohn's disease (CD) (ratio: 1.1). Mean diagnostic delay was 6.8 months for CD and 4.1 months for UC, with a significant reduction for CD when comparing the three-time intervals (p =0.008). The most frequent disease locations according to the Paris classification were ileocolonic for CD (41.3%) and pancolitis for UC (54.6%). Conclusions: The minimal incidence rate in Italy seems to have stabilized over the last two decades, even if it has increased when compared to previous reports. UC is still slightly more prevalent than CD in our country. Diagnostic delay significantly decreased for CD, reflecting an improved diagnostic capacity.

Metastases account for the majority of prostate cancer (PCa) deaths, and targeting them is a major goal of systemic therapy. We identified a novel interaction between two kinases: tousled-like kinase 1 (TLK1) and MAP kinase-activated protein kinase 5 (MK5) that promotes PCa spread. In PCa progression, TLK1-MK5 signalling appears to increase following antiandrogen treatment and in metastatic castration-resistant prostate cancer (mCRPC) patients. Determinations of motility rates (2D and 3D) of different TLK1- and MK5-perturbed cells, including knockout (KO) and knockdown (KD), as well as the use of specific inhibitors, showed the importance of these two proteins for in vitro dissemination. We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. Expression of MK5-S354A or kinase-dead MK5 in MK5-depleted mouse embryonic fibroblast (MEF) cells failed to restore their motility compared with that of wild-type (WT) MK5-rescued MK5

The current European Society of Cardiology (ESC) Heart Failure Guidelines are the most comprehensive ESC document covering heart failure to date; however, the section focused on acute heart failure remains relatively too concise. Although several topics are more extensively covered than in previous versions, including some specific therapies, monitoring and disposition in the hospital, and the management of cardiogenic shock, the lack of high-quality evidence in acute, emergency, and critical care scenarios, poses a challenge for providing evidence-based recommendations, in particular when by comparison the data for chronic heart failure is so extensive. The paucity of evidence and specific recommendations for the general approach and management of acute heart failure in the emergency department is particularly relevant, because this is the setting where most acute heart failure patients are initially diagnosed and stabilized. The clinical phenotypes proposed are comprehensive, clinically relevant and with minimal overlap, whilst providing additional opportunity for discussion around respiratory failure and hypoperfusion. F.P. has received research grants from Abbott, Becton Dickenson, Brainbox, Calcimedica, CSL Behring, Cue, Ortho Clinical Diagnostics, Relypsa, Roche, Salix, Siemens. Consultant: Abbott, Astra-Zeneca, Beckman, Bosch, Fast Biomedical, Forrest Devices, Ischemia Care, Dx, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Osler, Relypsa, Roche, Quidel, Salix, Siemens, Upstream and has stock/ownership interests in AseptiScope Inc, Brainbox Inc, Braincheck Inc, Coagulo Inc, Comprehensive Research Associates LLC, Comprehensive Research Management Inc, Emergencies in Medicine LLC, Fast Inc, Forrest Devices, Ischemia DX LLC, Lucia Inc, Prevencio Inc, ScPharma, Trivirum Inc, Upstream Inc. E.P.’ employer has received support from Novartis for consulting work and she has consulted for scPharmaceuticals outside of the submitted work. She has received research support from the NIH (R01HL148439). Sí

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.

Purpose This study aimed to analyze biometry values cutoffs for the choice of the best intraocular lens power calculation formula for AcrySof IQ Vivity intraocular lens. Methods The study was designed as interventional case series with 3 months of follow-up. Intraocular lens power calculation formulas included Barrett Universal II and SRK/T. The first was adopted for the intraocular lens power choice. The quantitative analysis focused on the identification of specific biometric cutoffs considering axial length, anterior chamber depth, and corneal powers. We included only the dominant eye in the statistical analysis. Results One hundred and eight eyes of 54 patients (23 males; mean age 62 ± 5 years) with no ocular diseases were included. Best-corrected visual acuity improved from 0.3 ± 0.2 to 0.0 ± 0.0 logMAR. All the eyes reached spectacles-free far and intermediate visions; a spherical addition of + 1.0D was necessary to adjust near vision. We identified significant quantitative cutoffs based on axial length and anterior chamber depth. Barrett Universal II resulted the best formula for eyes disclosing an axial length >25 mm, whereas SRK/T turned out to be the best choice for the eyes characterized by an anterior chamber depth Conclusions Axial length and anterior chamber depth influence the choice of Barrett Universal II and SRK/T formulas. Quantitative biometric cutoffs may be useful to discriminate the best formula to be adopted.

ObjectivesTo evaluate the potential of soluble cluster of differentiation 146 (sCD146) in the detection and grading of congestion in patients with acute dyspnoea.DesignSubanalysis of the prospective observational Lithuanian Echocardiography Study of Dyspnoea in Acute Settings (LEDA) cohort.SettingTwo Lithuanian university centres.ParticipantsAdult patients with acute dyspnoea admitted to the emergency department.MethodsCongestion was assessed using clinical and sonographic parameters. All patients underwent sCD146 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing.ResultsThe median value of sCD146 concentration in the study cohort (n=437) was 405 (IQR 315–509) ng/mL. sCD146 was higher in patients with peripheral oedema than in those without (median (IQR) 472 (373–535) vs 400 (304–501) ng/mL, p=0.009) and with pulmonary rales than in those without (439 (335–528) vs 394 (296–484) ng/mL, p=0.001). We found a parallel increase of estimated right atrial pressure (eRAP) and sCD146 concentration: sCD146 was 337 (300–425), 404 (290–489) and 477 (363–572) ng/mL in patients with normal, moderately elevated and high eRAP, respectively (p=0.001). In patients with low NT-proBNP, high sCD146 distinguished a subgroup with a higher prevalence of oedema as compared with patients with low levels of both biomarkers (76.0% vs 41.0%, p=0.010). Moreover, high sCD146 indicated a higher prevalence of elevated eRAP, irrespective of NT-proBNP concentration (pConclusionsCD146 concentration reflects the degree of intravascular and tissue congestion assessed by clinical and echocardiographic indices, with this association maintained in patients with low NT-proBNP. Our data support the notion that NT-proBNP might represent heart stretch while sCD146 rather represents peripheral venous congestion.

Objectives and study There is a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children. Methods Fifteen videos of follow-up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or Simple Endoscopic Score for Crohn Disease (SES-CD). Scores from all reviewers were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores' reliability. Results Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13-0.55) for ulcerative colitis (UC) and 0.266 (0.11-0.52) for Crohn disease (CD). When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss kappa coefficient was 0.408 (0.29-0.53) for UC and 0.552 (0.43-0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321-0.854). In multivariable analysis, none of the reviewer's characteristics affected the readers' errors. Conclusions This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low-grade concordance with the expert adult gastroenterologist's evaluations. Future-specific training programs should be considered to increase IOA in using IBD endoscopic activity scores.

The primary aim of this study was to describe the use of primary anti-infective prophylaxis (AP) in common clinical practice in patients affected by immune thrombocytopenia (ITP) and treated with RTX. Population studied consisted of patients affected by ITP (age ≥ 18 years) who had received at least one dose of RTX from January 2008 to June 2018. Five Italian haematology centres participated in the current study. Data were retrospectively collected: demographic data (age, gender), concomitant comorbidities and previous therapies for ITP, characteristics of AP, the occurrence of infections and their management. The ITP cohort consisted of 67 patients sub-grouped into two categories according to the administration of AP: (1) treated with AP (N= 34; 51%) and (2) not treated with AP (N=33, 49%). AP consisted of combined trimethoprim/sulfamethoxazole (TMP/SMX) and acyclovir (AC) in half of patients. TPM/SMX as a single agent was adopted in 32% patients and one patient received only AC. Overall, infections were experienced in 15% of patients during follow-up with a similar proportion in the 2 groups (treated and not treated) of patients (14.7% vs 15%). Clinical course of infections was however, less severe in patients treated with AP, where all infections were grade 2 and did not require hospitalization. In neither group of patients was reported Pneumocystis pneumonia. In conclusion, despite the absence of clear evidence, our analysis shows that AP in patients with ITP receiving RTX is frequently adopted, even if in the absence of well-defined criteria. Prophylaxis administration is quite consistent within the same haematological Center; thus, it seems related to clinicians' experience.

Background: To perform a quantitative optical coherence tomography (OCT) angiography (OCTA) analysis of macular neovascularization (MNV) secondary to age-related macular degeneration (AMD), central serous chorioretinopathy (CSC) and best vitelliform macular dystrophy (BVMD), with the aim of highlighting quantitative features indicating different clinical entities. Methods: Study design: prospective, interventional. We recruited patients affected by AMD, CSC or BVMD, complicated by naive MNV. All patients underwent complete ophthalmologic examination and multimodal imaging. They were treated with anti-VEGF injections, following a pro-re-nata regimen. The ensuing follow-up lasted 1 year. Quantitative dye-based angiography, OCT, and OCTA parameters were analysed to obtain cutoff values able to distinguish two clinically different patient subgroups for each retinal disease. The main outcome measures were best-corrected visual acuity (BCVA), central macular thickness, vessel density of superficial, deep and choriocapillaris plexa, vessel tortuosity (VT) of MNV, vessel dispersion of MNV, number of injections, MNV/leakage ratio, MNV size, speckled fluorescence, and outer retinal atrophy. Results: Ninety-eight eyes affected by MNV (98 patients) were analysed. These included 66 eyes affected by AMD, 18 displaying CSC, and 14 eyes with BVMD. BCVA was alike in the three groups, both at baseline and after 1 year (p > 0.05). An MNV VT cutoff of 8.40 at baseline detected two patient subgroups differing significantly in terms of morpho-functional features, found both at baseline and at the end of the follow-up. Conclusions: Quantitative OCTA suggested that the MNV’s VT might be able to provide a better characterization of two different morpho-functional manifestations in AMD, CSC and BVMD.

Embaràs i malaltia cardíaca; Resultats de l’embaràs; Transposició de les grans artèries Embarazo y enfermedad cardíaca; Resultados del embarazo; Transposición de las grandes arterias Pregnancy and cardiac disease; Pregnancy outcomes, Transposition of the great arteries Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate. Funding from “Zabawas Foundation” and “De Hoop Foundation” in addition to the support from EURObservational Research Programme (EORP) is greatly acknowledged. Since the start of EORP, the following companies have supported the program: Abbott Vascular Int (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014–2017), Edwards (2016–2019), Gedeon Richter Plc (2014–2016), Menarini Int Op (2009–2012), MSD‐Merck & Co (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2009–2021), and Vifor (2019–2022).

BackgroundTo analyse multimodal imaging alterations in the subclinical form of best vitelliform macular dystrophy (BVMD).MethodsThe study was designed as an observational, cross-sectional case series. Eleven eyes of 7 subclinical patients with BVMD and 12 age-matched and sex-matched controls were included. Multimodal imaging included fundus blue-light autofluorescence, near-infrared autofluorescence (NIR-AF), structural optical coherence tomography (OCT) and OCT angiography (OCTA). The quantitative analysis included the calculation of the following parameters: vessel density (VD), vessel tortuosity (VT), vessel dispersion (Vdisp), vessel rarefaction (VR), foveal avascular zone (FAZ) area, reflectivity of the outer retinal bands and choriocapillaris porosity (CCP).ResultsMean best-corrected visual acuity was 0.0±0.0 LogMAR in both groups. The round central hypoautofluorescent alteration on NIR-AF corresponded to a significant reflectivity attenuation of the outer retinal bands on structural OCT (0.55±0.18 vs 0.75±0.08; p0.05). The FAZ area turned out to be significantly restricted at the level of the deep capillary plexus in subclinical BVMD eyes (pConclusionsThe subclinical stage of BVMD is characterised by significant alterations of the outer retinal bands and the choriocapillaris. Quantitative multimodal imaging assessment suggests that subclinical BVMD is affected by the functional impairment of the outer retinal structures, leading to an alteration in melanin and growth factor production.

Biallelic loss-of-function (LoF) variants in CENPF gene are responsible for Stromme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from -2.9 SDS to -5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted-V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Stromme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case-series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Stromme syndrome.

International audience; OBJECTIVE: This initial study aimed to investigate the feasibility of simultaneously measuring perfusion and diffusion including kurtosis features in acute ischemic stroke with the combined intravoxel incoherent motion and non-Gaussian diffusional kurtosis imaging (DKI-IVIM). MATERIAL AND METHODS: Five ischemic stroke patients underwent a 4-minute diffusion weighted imaging (DWI) protocol, using 8 b values chosen with the Cramer-Rao-Lower-Bound optimization approach, in addition to conventional DWI and arterial spin labeling sequences. Regions of interest in pathological and control regions were analyzed with DKI-IVIM, and parametric maps were reconstructed. RESULTS: The IVIM diffusion coefficient (D) decreased (P < 0.0001) in the infarcted areas, whereas higher kurtosis coefficient values were found (P = 0.0002). Regarding the perfusion, the individual IVIM perfusion fraction f decreased in 3 matching cases with the cerebral blood flow estimated through arterial spin labeling and the fD* decreased only in 2 patients of those. CONCLUSIONS: When compared with conventional stroke imaging protocol, DKI-IVIM 4-minute 2-in-1 acquisition can provide diffusion results comparable with conventional DWI with complementary kurtosis estimations but a limited robustness regarding perfusion estimations for clinical purpose.

Even though no definitive link has been established, Bell's palsy has been described as a potential side effect of SARS-CoV-2 mRNA vaccines in a few reports, and the US Food and Drug Administration has recommended strict surveillance of its occurrence in the vaccinated general population. We present the case of a previously healthy 35-year-old female patient who developed Bell's palsy 12 h after receiving the first dose of the mRNA-1273 vaccine. Her general practitioner performed the diagnosis, and corticosteroid treatment was initiated, with slow symptoms improvement. The neurologist's evaluation and a contrast-enhanced brain Magnetic Resonance Imaging revealed a subtle enhancement of the left facial nerve, confirming the diagnosis of Bell's palsy.

Background Aspartate aminotransferase (AST) is often increased in COVID-19 and, in some studies, AST abnormalities were associated with mortality risk. Methods 2054 hospitalized COVID-19 patients were studied. To identify sources of AST release, correlations between AST peak values and other biomarkers of tissue damage, i.e., alanine aminotransferase (ALT) for hepatocellular damage, creatine kinase (CK) for muscle damage, lactate dehydrogenase for multiorgan involvement, alkaline phosphatase and γ-glutamyltransferase for cholestatic injury, and C-reactive protein (CRP) for systemic inflammation, were performed and coefficients of determination estimated. The role of AST to predict death and intensive care unit admission during hospitalization was also evaluated. All measurements were performed using standardized assays. Results AST was increased in 69% of patients. Increases could be fully explained by summing the effects of hepatocellular injury [AST dependence from ALT, 66.8% [95% confidence interval (CI): 64.5–69.1)] and muscle damage [AST dependence from CK, 42.6% (CI: 39.3–45.8)]. We were unable to demonstrate an independent association of AST increases with worse outcomes. Conclusion The mechanisms for abnormal AST in COVID-19 are likely multifactorial and a status related to tissue suffering could play a significant role. The clinical significance of AST elevations remains unclear.

Introduction: Inclisiran is a novel posttranscriptional gene silencing therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis by RNA interference and has a potent, dose-dependent, durable effect in lowering LDL-C, and therefore is an effective drug to treat dyslipidemia, reducing the risk for acute cardiovascular (CV) events. It is safe and well-tolerated. Areas covered: This paper aims to review the mechanism of action of inclisiran while evaluating its efficacy and safety in the treatment of dyslipidemia from data of the clinical trials in the ORION program. Expert opinion: Data from the clinical trials in the ORION program demonstrated efficacy and safety of inclisiran in patients with dyslipidemia. Adverse events were similar in the inclisiran and placebo groups in the clinical trials, although injection-site reactions were more frequent with inclisiran than with placebo. Although the combination of efficacy and safety makes inclisiran a good option for the treatment of dyslipidemia compared to other PCSK9 targeting therapeutic strategies, however, further studies should exclude the possibility that inclisiran, through lower-affinity interactions, may influence other mRNAs in the physiological milieu.

Introduction: The purpose of this study is to report the stone free rate (SFR) and clinical complications in patients submitted to retrograde intrarenal surgery (RIRS). Materials and methods: A total of 571 procedures of upper urinary stones treated using flexible ureteroscopy and holmium laser lithotripsy from January 2014 to February 2020 have been analyzed. Overall SFR was evaluated after 3 months following the procedure by means of a non-contrast computed tomography. Success was considered as stone-free status or ≤ 0.4 cm fragments. Results: The overall SFR was 92.3% in group 1 (stone size: < 1 cm), 88.3% in group 2 (stone size: > 1 ≤ 2 cm), 56.7% in group 3 (stone size: 2-3 cm) and 69.6% in group 4 (multiple stones). Post-operative complications, according to the Clavien- Dindo (CD) classification system, were recorded in 32 (5.6%) procedures. The major complications recorded were: one case of subcapsular hematoma (SRH) associated with pulmonary embolism two days after the procedure (CD Grade IIIa) treated conservatively and one case of hemorrhagic shock 2 hour with multiple renal bleedings requiring urgent nephrectomy (CD Grade IVA). Conclusions: The RIRS is an effective and safe procedure with a high SFR significantly correlated with the stone size; at the same time, RIRS could be characterized by severe clinical complications that require rapid diagnosis and prompt treatment.

Introduction The objective of this research was to evaluate and compare linear and surface accuracy of dental models fabricated using 3 different vat photopolymerization printing units: digital light synthesis (M2 Printer; Carbon, Redwood City, Calif), digital light processing (Juell 3D Flash OC; Park Dental Research, New York, NY), and stereolithography apparatus (Form 2; Formlabs Inc, Somerville, Mass), and a material jetting printing unit: PolyJet (Objet Eden 260VS; Stratasys, Eden Prairie, Minn). Methods Maxillary and mandibular dental arches of 20 patients with the American Board of Orthodontics Discrepancy Index scores ranging between 10 and 30 were scanned using an intraoral scanner. Stereolithographic files of each patient were printed via the 3-dimensional (3D) printers and were digitized again using a 3D desktop scanner to enable comparisons with the original scan data. One-sample t test and linear regression analyses were performed. To further graphically examine the accuracy between the different methods, Bland-Altman plots were computed. The level of significance was set at P Results Bland-Altman analysis showed no fixed bias of one approach vs the other, and random errors were detected in all linear accuracy comparisons. When a 0.25 mm tolerance level was deemed acceptable for any positive or negative surface changes, only the models manufactured from digital light processing and PolyJet units showed more than 97% match with the original scans. Conclusion The surface area of 3D printed models did not yield an utterly identical match to the original scan data and was affected by the type of printer. The clinical relevance of the differences observed on the 3D printed dental model surfaces requires application-specific judgments.

Transgenic breast cancer mouse models are critical tools for preclinical studies of human breast cancer. Genetic editing of the murine mammary gland allows for modeling of abnormal genetic events frequently found in human breast cancers. Genetically engineered mouse models (GEMMs) of breast cancer employ tissue-specific genetic manipulation for tumorigenic induction within the mammary tissue. Under the transcriptional control of mammary-specific promoters, transgenic mouse models can simulate spontaneous mammary tumorigenesis by expressing one or more putative oncogenes, such as MYC, HRAS, and PIK3CA. Alternatively, the Cre-Lox system allows for tissue-specific deletion of tumor suppressors, such as p53, Rb1, and Brca1, or specific knock-in of putative oncogenes. Thus, GEMMs can be designed to implement one or more genetic events to induce mammary tumorigenesis. Features of GEMMs, such as age of transgene expression, breeding quality, tumor latency, histopathological characteristics, and propensity for local and distant metastasis, are variable and strain-dependent. This review aims to summarize currently available transgenic breast cancer mouse models that undergo spontaneous mammary tumorigenesis upon genetic manipulation, their varying characteristics, and their individual genetic manipulations that model aberrant signaling events observed in human breast cancers.

In the world reference context, although virtual reality, augmented reality and mixed reality have been emerging methodologies for several years, only today technological and scientific advances have made them suitable to revolutionize clinical care and medical contexts through the provision of enhanced functionalities and improved health services. This systematic review provides the state-of-the-art applications of the Microsoft® HoloLens 2 in a medical and healthcare context. Focusing on the potential that this technology has in providing digitally supported clinical care, also but not only in relation to the COVID-19 pandemic, studies that proved the applicability and feasibility of HoloLens 2 in a medical and healthcare scenario were considered. The review presents a thorough examination of the different studies conducted since 2019, focusing on HoloLens 2 medical sub-field applications, device functionalities provided to users, software/platform/framework used, as well as the study validation. The results provided in this paper could highlight the potential and limitations of the HoloLens 2-based innovative solutions and bring focus to emerging research topics, such as telemedicine, remote control and motor rehabilitation.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

Background: To evaluate the relationship between superficial, deep foveal avascular zone (FAZ) and foveal cyst areas in eyes with cystoid macular oedema (CMO) associated with gyrate atrophy of the choroid and retina (GA). Methods: This is a retrospective collaborative multicenter study of optical coherence tomography-angiography (OCTA) images in GA. Superficial and deep FAZ and foveal cyst were measured using Image J by two independent experts. Values were corrected for myopia magnification. These values were compared with age-matched controls from normative data. Results: Twenty-three eyes from 12 patients with GA and CMO were included in the study. The mean ± standard deviation age was 22 ± 19.7 years, mean Snellen spectacle-corrected visual acuity of 20/70 with mean myopia of 5.7 ± 4.1 dioptres. Qualitatively, no focal occlusion of superficial and deep capillary plexus was noted. Mean superficial FAZ area (0.484 ± 0.317 mm2), deep FAZ area (0.626 ± 0.452 mm2), and foveal cyst area (0.630 ± 0.503 mm2) were significantly larger than superficial and deep FAZ areas in controls of same age range (p < 0.001). Macular cyst area correlated with superficial FAZ area (R = 0.59; p = 0.0057) and more strongly with deep FAZ area (R = 0.69; p < 0.001). Conclusions: The superficial and deep FAZ area in GA-associated CMO were noted to be significantly larger than in controls. It seems that RPE dysfunction leads to foveal cyst enlargement displacing the capillary plexus with resultant enlarged superficial and deep FAZ area.

The exact prediction of outcome of patients with Merkel cell carcinoma (MCC) of the skin is difficult to determine, although several attempts have been made to identify clinico-pathologic prognostic factors. The Ki67 proliferative index is a well-known marker routinely used to define the prognosis of patients with neuroendocrine neoplasms. However, its prognostic value has been poorly investigated in MCC, and available published results are often contradictory mainly because restricted to small series in the absence of standardized methods for Ki67 evaluation. For this reason, we explored the potential prognostic role of Ki67 proliferative index in a large series of MCCs using the WHO standardized method of counting positive cells in at least 500 tumor cells in hot spot areas on camera-captured printed images. In addition, since MCC may be considered as the cutaneous counterpart of digestive neuroendocrine carcinomas (NECs), we decided to stratify MCCs using the available and efficient Ki67 threshold of 55%, which was found prognostic in digestive NECs. This choice was also supported by the Youden index analysis. In addition, we analyzed the prognostic value of other clinico-pathologic parameters using both univariate and multivariate analysis. Ki67 index appeared significantly associated with prognosis at univariate analysis together with stage IV, lack of MCPyV, and p63 expression, but not at the multivariate analysis, where survival resulted independently influenced by p63 expression and tumor stage, only.

Background To assess retinal layer thickness in choroideremia (CHM) and to reveal its correlation with optical coherence tomography (OCT) angiography (OCTA) findings. Methods The study was designed as an observational, cross-sectional clinical series of patients with CHM, which included 14 CHM eyes and 14 age-matched controls. Multimodal imaging included OCT and OCTA. The vessel density (VD) of superficial capillary (SCP), deep capillary (DCP) and choriocapillaris (CC) plexuses was analysed by OCTA. The apparently preserved retinal islet and atrophic regions were investigated separately. Main outcome measures were as follows: best-corrected visual acuity (BCVA), total retinal layers, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), ellipsoid zone–retinal pigment epithelium (EZ-RPE) layer, choroidal thickness and VDs of SCP, DCP and of CC. Results Mean BCVA was 0.0±0.0 LogMAR in both groups. GCL, ONL, EZ-RPE and choroid were significantly thinned in CHM, particularly in the atrophic region. OPL was unaffected in the apparently preserved islet, whereas INL and IPL were similarly thinned in the atrophic and apparently preserved retina. DCP appeared severely affected in both regions, while CC was only altered in the atrophic retina. Significant correlations were found between OCT and OCTA parameters. Conclusions Our study showed severe alterations in both outer and inner retinal layers of patients with CHM. The extended retinal involvement might be the consequence of neuronal and vascular trophic factor reduction produced by the primarily altered RPE and/or secondary Müller glial cell reaction.

Recent advances in tumor immunology, fostered by dramatic outcomes with cancer immunotherapy, have opened new scenarios in cancer metastasis. The cancer stemness/mesenchymal phenotype and an excess of immune suppressive signals are emerging as Intertwined aspects of human tumors. This review examines recent studies that explored the mechanistic links between cancer cell stemness and immunoevasion, and the evidence points to these key events in cancer metastasis as two sides of the same coin. This review also covers the mechanisms involved in tumor expression of programmed cell death ligand 1 (PD-L1), a major factor exploited by human neoplasias to suppress immune control. We highlight the convergence of mesenchymal traits and PD-L1 expression and examine the functions of this immune inhibitory molecule, which confers cancer cell resistance and aggressiveness.

[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

The literature reported higher depression rates in psoriasis patients compared to the general population. Our study aimed to verify whether variability in depression prevalence was due to using different diagnostic tools. We also aimed to determine whether dysfunctional coping strategies might increase the depression burden. We assessed psoriasis severity by the Psoriasis Area Severity Index (PASI) and PSOdisk. We analyzed mental alterations of 120 outpatients by Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A), Symptom Checklist-90-Revised (SCL-90-R), plus coping strategies and quality of life by Coping Orientation to Problems Experienced (COPE) Inventory and 36-Item Short Form Health Survey (SF-36). We divided our cohort into five subgroups from minimal to severe psoriasis using the PSOdisk total score. Depression prevalence varied according to the assessment criteria for specificity, frequency, and severity. Different mood disorders other than major depression emerged when we used DSM-IV-TR criteria. Correlation analysis of the criteria we used to diagnose depression or depressed mood indicated that a dysfunctional coping strategy was highly and positively correlated only in patients of the severe subgroup. Differently, a negative correlation emerged between the SF-36 Mental Summary Component (MSC) and behavioral disengagement, thus suggesting that psychopathological distress might induce patients with a marked/severe psoriasis to adopt dysfunctional coping strategies. Dermatologists are fundamental in detecting comorbid depression, referring psoriasis patients to mental health specialists to achieve adequate treatments, and preventing suicide risk.

Atherosclerosis is responsible for large cardiovascular mortality in many countries globally. It has been shown over the last decades that the reduction of atherosclerotic progression is a critical factor for preventing future cardiovascular events. Low-density lipoproteins (LDL) have been successfully targeted, and their reduction is one of the key preventing measures in patients with atherosclerotic disease. LDL particles are pivotal for the formation and progression of atherosclerotic plaques; yet, they are quite heterogeneous, and smaller, denser LDL species are the most atherogenic. These particles have greater arterial entry and retention, higher susceptibility to oxidation, as well as reduced affinity for the LDL receptor. Increased proportion of small, dense LDL particles is an integral part of the atherogenic lipoprotein phenotype, the most common form of dyslipidemia associated with insulin resistance. Recent data suggest that both genetic and epigenetic factors might induce expression of this specific lipid pattern. In addition, a typical finding of increased small, dense LDL particles was confirmed in different categories of patients with elevated cardiovascular risk. Small, dense LDL is an independent risk factor for cardiovascular diseases, which emphasizes the clinical importance of both the quality and the quantity of LDL. An effective management of atherosclerotic disease should take into account the presence of small, dense LDL in order to prevent cardiovascular complications.

Introduction: Hypertension is the biggest contributor to the global burden of cardiovascular diseases and related death, but the rates of hypertension awareness, treatment, and control remain largely perfectible. Methods: During the XVII World Hypertension Day (May 17th, 2021), a nationwide cross-sectional opportunistic study endorsed by the Italian Society of Hypertension was conducted on volunteer adults ≥18years to raise awareness of high blood pressure (BP). A questionnaire on major demographic/clinical features (sex, age, employment, education, BP status awareness, hypertension family/personal history, antihypertensive medications use) and BP measurement habits (≥1 BP measurement in the previous month/week) was administered. Due to the ongoing SARS-CoV-2 pandemic, BP was measured with standard procedures in a subset of participants (24.4%). Results: A total of 1354 participants (mean age 56.3±15.3years; 57.3% women; mean BP: 131.2±17.5/81.6±10.5mmHg; 42.3% self-declared hypertensive; 41.4% on antihypertensive medications) were enrolled; 73.6% declared being aware of their BP status. Among treated individuals with measured BP, 26.9% showed BP levels within the predefined therapeutic goals. Interestingly, BP status awareness rates were the highest among individuals with uncontrolled hypertension (85.1%) and the lowest among those with normal measured BP (54.4%). Conclusions: This survey provides an updated insight into hypertension awareness and control in a setting of daily clinical practice, emphasizing the centricity of patients in the therapeutic alliance for a successful reduction of cardiovascular risk.

Background and aim: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. Methods and results: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA

Background Cyclic Vomiting Syndrome (CVS) is a rare functional gastrointestinal disorder, which has a considerable burden on quality of life of both children and their family. Aim of the study was to evaluate the diagnostic modalities and therapeutic approach to CVS among Italian tertiary care centers and the differences according to subspecialties, as well as to explore whether potential predictive factors associated with either a poor outcome or a response to a specific treatment. Methods Cross-sectional multicenter web-based survey involving members of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP). Results A total of 67 responses were received and analyzed. Most of the respondent units cared for less than 20 patients. More than half of the patients were referred after 3 to 5 episodes, and a quarter after 5 attacks. We report different diagnostic approaches among Italian clinicians, which was particularly evident when comparing gastroenterologists and neurologists. Moreover, our survey demonstrated a predilection of certain drugs during emetic phase according to specific clinic, which reflects the cultural background of physicians. Conclusion In conclusion, our survey highlights poor consensus amongst clinicians in our country in the diagnosis and the management of children with CVS, raising the need for a national consensus guideline in order to standardize the practice.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.

Introduction: Bempedoic acid is a first-in-class low-density lipoprotein cholesterol (LDL-C) lowering agent which offers an important opportunity for further LDL-C lowering in statin-intolerant patients or in patients requiring further LDL-C reduction despite maximally tolerated statin therapy.Areas covered: In this review, we examined the pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of bempedoic acid, based on randomized clinical phase III clinical studies and their meta-analyses.Expert opinion: Unlike statins, bempedoic acid is administered as a prodrug and is converted to active form by a liver-specific enzyme. For the liver-specific mechanism of action, bempedoic acid has the potential to reduce the risk of muscle-related adverse events which can limit the utilization and effectiveness of statin therapy.