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Abstract Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9–18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.

Abstract Background Lung ultrasonography (LUS) is a non-invasive imaging method used to diagnose and monitor conditions such as pulmonary edema, pneumonia, and pneumothorax. It is precious where other imaging techniques like CT scan or chest X-rays are of limited access, especially in low- and middle-income countries with reduced resources. Furthermore, LUS reduces radiation exposure and its related blood cancer adverse events, which is particularly relevant in children and young subjects. The score obtained with LUS allows semi-quantification of regional loss of aeration, and it can provide a valuable and reliable assessment of the severity of most respiratory diseases. However, inter-observer reliability of the score has never been systematically assessed. This study aims to assess experienced LUS operators’ agreement on a sample of video clips showing predefined findings. Methods Twenty-five anonymized video clips comprehensively depicting the different values of LUS score were shown to renowned LUS experts blinded to patients’ clinical data and the study’s aims using an online form. Clips were acquired from five different ultrasound machines. Fleiss-Cohen weighted kappa was used to evaluate experts’ agreement. Results Over a period of 3 months, 20 experienced operators completed the assessment. Most worked in the ICU (10), ED (6), HDU (2), cardiology ward (1), or obstetric/gynecology department (1). The proportional LUS score mean was 15.3 (SD 1.6). Inter-rater agreement varied: 6 clips had full agreement, 3 had 19 out of 20 raters agreeing, and 3 had 18 agreeing, while the remaining 13 had 17 or fewer people agreeing on the assigned score. Scores 0 and score 3 were more reproducible than scores 1 and 2. Fleiss’ Kappa for overall answers was 0.87 (95% CI 0.815–0.931, p

Abstract Purpose Although insecure attachment and interpersonal problems have been acknowledged as risk and maintaining factors of eating disorders (EDs), the mediating role of interpersonal problems between attachment style and ED psychopathology has been poorly explored. The purpose of this study was to investigate the mediating role of interpersonal problems between insecure attachment and ED psychopathology. Methods One-hundred-nine women with anorexia nervosa and 157 women with bulimia nervosa filled in the Eating Disorder Inventory-2 (EDI-2) and the Experiences in Close Relationships (ECR) revised scale to assess ED core symptoms and attachment styles, respectively. Interpersonal difficulties were evaluated by the Inventory of Interpersonal Problems (IIP-32). A mediator’s path model was conducted with anxious and avoidant attachment subscores as independent variables, ED core symptoms as dependent variables and interpersonal difficulties as mediators. The diagnosis was entered in the model as a confounding factor. Results The socially inhibited/avoidant interpersonal dimension was a mediator between avoidant attachment and the drive to thinness as well as between avoidant attachment and body dissatisfaction. An indirect connection was found between attachment-related anxiety and bulimic symptoms through the mediation of intrusive/needy score. Conclusions Social avoidance and intrusiveness mediate the relationships between avoidant and anxious attachment styles and ED psychopathology. These interpersonal problems may represent specific targets for psychotherapeutic treatments in individuals with EDs and insecure attachment. Level of evidence Level III: Evidence obtained from well-designed cohort or case–control analytic studies.

Objective: A case of post-neurosurgical ventriculitis caused by a KPC-producing Klebsiella pneumoniae (KPC-Kp) with a ceftazidime/avibactam-resistant, meropenem-susceptible phenotype is reported. Methods and results: The patient had a concomitant bloodstream infection with a wild-type KPC-Kp with a ceftazidime/avibactam-susceptible, meropenem-resistant phenotype. Prolonged treatment with intravenous fosfomycin and meropenem/vaborbactam achieved clinical success.Therapeutic drug monitoring performed during the first days of treatment showed for the first time that vaborbactam efficiently penetrates cerebrospinal fluid. In contrast, meropenem was undetectable in cerebrospinal fluid at each sampling, suggesting that additional doses of meropenem may be required to appropriately prescribe meropenem/vaborbactam for central nervous system infections. Plasma and cerebrospinal fluid levels of fosfomycin were adequate, confirming the potential of this agent possibly even in the fight against multidrug-resistant organisms. Conclusions: This case highlights the need for therapeutic drug monitoring as a crucial tool for optimizing treatment in complicated cases where the pharmacokinetic behaviour of antibiotics is difficult to predict.

Introduction: Childhood maltreatment, particularly emotional abuse (EA), has been identified as a significant risk factor for the development of eating disorders (EDs). This study investigated the association between EA and ED symptoms while considering multiple potential mediators. Methods: Participants included 151 individuals with Anorexia Nervosa (AN), 115 with Bulimia Nervosa (BN), and 108 healthy controls. The Childhood trauma questionnaire, the Toronto Alexithymia scale, the Behavioral inhibition System, and the Eating Disorder Inventory 2 scale were completed before treatment. A mediator path model was conducted in each group: EA was set as independent variable, eating symptoms as dependent variables and ineffectiveness, sensitivity to punishment, alexithymia, and impulsivity as mediators. Results: In individuals with AN, impulsivity emerged as a significant mediator between EA and desire for thinness and bulimic behaviors. Conversely, in individuals with BN, sensitivity to punishment was found to mediate the association between EA and dissatisfaction with one's body.Ineffectiveness and difficulty identifying emotions were identified as transdiagnostic mediators in both clinical groups. No mediation effect was found in healthy individuals. Discussion: The simultaneous assessment of multiple mediators in a unique model outlines the complex interplay between childhood EA and ED psychopathology. Improving ineffectiveness, emotion identification, sensitivity to punishment and impulsivity and exploring their relations with early emotional abuse may represent treatment targets in individuals with EDs and childhood trauma.

Introduction: Bone mineral density (BMD) is reduced in patients with human immunodeficiency virus (HIV) infection. Trabecular bone score (TBS) is an additional feature calculated by dual-energy X ray absorption (DXA) that measures texture inhomogeneity at lumbar spine level, providing an index of bone microarchitecture. However, its clinical value still needs to be fully addressed. Aims of the study were to assess BMD and TBS in a cohort of patients with HIV compared to a population of healthy subjects and to investigate the prognostic value of TBS in HIV infected patients. Method: Bone health was assessed by DXA in 165 patients with HIV infection (120 men, mean age 40 ± 7 years) and in 164 healthy subjects (53 male, mean age 37 ± 10 years). BMD was measured at level of lumbar spine (L1-L4), femoral neck and total hip. TBS was computed from the images of lumbar spine using machine proprietary software. Results: BMD at femoral neck level was similar in HIV infected patients and healthy subjects (p = 0.57), whereas BMD measured in total femur was lower in HIV infected patients compared to healthy subjects (p

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Abstract Over the last 20 years, advances in point-of-care lung ultrasound (PoCLUS) have been consistent. The clinical application of PoCLUS has drastically changed the diagnosis of some respiratory conditions mainly in the acute setting. Despite these improvements, misconceptions regarding the current scientific evidence and errors in the direction given to the latest research are delaying the implementation of PoCLUS in the clinical field. The diagnostic power of PoCLUS is still under-evaluated in many settings and there is a generalized yet unjustified feeling that further evidence is needed before introducing PoCLUS as a standard of care. In the effort to build up further evidence by new studies, the role of randomized clinical trials is over-emphasized and gold standards used to investigate diagnostic accuracy of PoCLUS are sometimes not appropriate. Moreover, the sonographic patterns and techniques used to confirm the diagnoses not always are adapted to the patients’ clinical condition, which limit the scientific value of those clinical studies. Finally, there is a recurrent confusion in the role of PoCLUS scoring techniques, which should be only applied to quantify and monitor injury severity and not to diagnose lung diseases. Awareness of these misconceptions and errors could help the researchers when approaching new study projects on PoCLUS.

IntroductionReal-life experience with imipenem/cilastatin/relebactam (IMI/REL) for the treatment of KPC-producing Klebsiella pneumoniae complex (KPC-Kp) and difficult-to-treat resistance (DTR) Pseudomonas aeruginosa (DTR-PA) infections is herein described.MethodsAdult patients with KPC-Kp or DTR-PA infections who received ≥48 h of IMI/REL were included. Clinical and microbiological outcomes were retrieved through the medical records. Primary outcome was clinical cure. Secondary outcomes included mortality from infection onset and adverse effects attributable to IMI/REL.ResultsWe included 10 patients with different infections caused by DTR-PA (n = 4), KPC-Kp [n = 5, of which 3 ceftazidime/avibactam-resistant (CTV-R KPC-Kp), 2 CTV susceptible (CTV-S KPC-Kp)] or both DTR-PA/KPC-Kp (n = 1) successfully treated with IMI/REL: 3 hospital-acquired pneumonia, 1 ventilator-associated pneumonia, 2 skin and soft tissue infections, 1 osteomyelitis, 2 bloodstream infections, 1 complicated urinary tract infection. Clinical cure was achieved in all cases. No patients died and no side effect were reported.DiscussionWe reported the preliminary real-life experience on the successful and safe use of IMI/REL for the treatment of KPC-Kp or DTR-PA complicated infections, including pneumonia and bone infections.

Abstract Autosomal dominant pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease (PD). The most common mutation, G2019S-LRRK2, increases the kinase activity of LRRK2 causing hyper-phosphorylation of its substrates. One of these substrates, Rab10, is phosphorylated at a conserved Thr73 residue (pRab10), and is one of the most abundant LRRK2 Rab GTPases expressed in various tissues. The involvement of Rab10 in neurodegenerative disease, including both PD and Alzheimer’s disease makes pinpointing the cellular and subcellular localization of Rab10 and pRab10 in the brain an important step in understanding its functional role, and how post-translational modifications could impact function. To establish the specificity of antibodies to the phosphorylated form of Rab10 (pRab10), Rab10 specific antisense oligonucleotides were intraventricularly injected into the brains of mice. Further, Rab10 knock out induced neurons, differentiated from human induced pluripotent stem cells were used to test the pRab10 antibody specificity. To amplify the weak immunofluorescence signal of pRab10, tyramide signal amplification was utilized. Rab10 and pRab10 were expressed in the cortex, striatum and the substantia nigra pars compacta. Immunofluorescence for pRab10 was increased in G2019S-LRRK2 knockin mice. Neurons, astrocytes, microglia and oligodendrocytes all showed Rab10 and pRab10 expression. While Rab10 colocalized with endoplasmic reticulum, lysosome and trans-Golgi network markers, pRab10 did not localize to these organelles. However, pRab10, did overlap with markers of the presynaptic terminal in both mouse and human cortex, including α-synuclein. Results from this study suggest Rab10 and pRab10 are expressed in all brain areas and cell types tested in this study, but pRab10 is enriched at the presynaptic terminal. As Rab10 is a LRRK2 kinase substrate, increased kinase activity of G2019S-LRRK2 in PD may affect Rab10 mediated membrane trafficking at the presynaptic terminal in neurons in disease.

Stress profoundly affects physical and mental health, particularly when experienced early in life. Early-life stress (ELS) encompasses adverse childhood experiences such as abuse, neglect, violence, or chronic poverty. These stressors can induce long-lasting changes in brain structure and function, impacting areas involved in emotion regulation, cognition, and stress response. Consequently, individuals exposed to high levels of ELS are at an increased risk for mental health disorders like depression, anxiety, and post-traumatic stress disorders, as well as physical health issues, including metabolic disorders, cardiovascular disease, and cancer. This review explores the biological and psychological consequences of early-life adversity paradigms in rodents, such as maternal separation or deprivation and limited bedding or nesting. The study of these experimental models have revealed that the organism’s response to ELS is complex, involving genetic and epigenetic mechanisms, and is associated with the dysregulation of physiological systems like the nervous, neuroendocrine, and immune systems, in a sex-dependent fashion. Understanding the impact of ELS is crucial for developing effective interventions and preventive strategies in humans exposed to stressful or traumatic experiences in childhood.

BackgroundLeft bundle branch (LBB) pacing could achieve cardiac resynchronization therapy (CRT) in patients who cannot be resynchronized via the placement of the left ventricle (LV) lead into the coronary sinus. LBB pacing could improve cardiovascular outcomes in heart failure (HF) patients with LBB block who are affected by type 2 diabetes mellitus (T2DM).Study hypothesisLBB pacing could increase the number of CRT responders and lead to the best clinical outcomes in HF patients with T2DM, inducing cardiac remodeling and improving left ventricle ejection fraction (LVEF) via microRNA (miR) modulation.MethodsIn a multicenter observational study, we enrolled 334 HF patients with LBB block and an indication to receive LBB pacing for CRT. In these patients, we evaluated the CRT responder rate, clinical outcomes, and miR expression at 1 year of follow-up.ResultsAt 1 year of follow-up, we had 223 responders (66.8%), 132 hospitalizations for HF (39.5%), 24 cardiac deaths (7.2%), and 37 all-cause deaths (11.1%), with a higher rate of HF hospitalizations (77 (69.4%) vs 55 (24.7%), p < 0.05), and cardiac deaths (13 (11.7% vs 11 (4.9%), p < 0.05) in non-responders vs responders. At the end of follow-up, we found the lowest expression of miR-26, miR-29, miR-30, miR-92, and miR-145 in LBB-pacing non-responders vs responders (p < 0.05), and a direct correlation between miR-30 (0.340, [0.833–1.915]; p 0.001), the 6-minute-walking test (6MWT; 0.168, [0.008–0.060]; p 0.011), angiotensin-receptor-neprilysin inhibitors (ARNI; 0.157, [0.183–4.877]; p 0.035), sodium-glucose-transporter-2 inhibitors (0.245, [2.242–7.283]; p 0.001), and LVEF improvements. C reactive protein (CRP) inversely correlated with LVEF improvement (−0.220, [-(0.066–0.263)]; p 0.001). ARNI (1.373, CI 95% [1.007–1.872], p 0.045), miR-30 (2.713, CI 95% [1.543–4.769], p 0.001), and 6MWT (1.288, CI 95% [1.084–1.998], p 0.001) were predictors of LBB pacing responders at 1 year of follow-up.ConclusionLBB-pacing responders evidenced miR modulation, which was linked to significant improvement of the cardiac pump. Specifically, miR-30 was linked to cardiac pump improvement and predicted responders at 1 year of follow-up in patients with T2DM.

Introduction and aimsTreatment-resistant depression (TRD) occurs when at least two different antidepressants, taken at the right dosage, for adequate period of time and with continuity, fail to give positive clinical effects. Esketamine, the S-enantiomer of ketamine, was recently approved for TRD treatment from U.S. Food and Drug Administration and European Medicine Agency. Despite proved clinical efficacy, many misconceptions by clinicians and patients accompany this medication. We aimed to review the most common “false myths” regarding TRD and esketemine, counterarguing with evidence-based facts.MethodsThe keywords “esketamine”, “treatment resistance depression”, “depression”, “myth”, “mythology”, “pharmacological treatment”, and “misunderstanding” were entered in the main databases and combined through Boolean operators.ResultsMisconceptions regarding the TRD prevalence, clinical features and predictors have been found. With respect of esketamine, criteria to start treatment, dissociative symptoms, potential addiction and aspects of administration and monitoring, were found to be affected by false beliefs by clinicians and patients.Discussion and conclusionTRD represents a challenging condition, requiring precise diagnosis in order to achieve patient’s full recovery. Esketamine has been proved as an effective medication to treat TRD, although it requires precautions. Evidence can inform clinical practice, in order to offer this innovative treatment to all patients with TRD.

Background: Psoriasis is a chronic skin disorder affecting 2–3% of the global population, and is associated with several comorbidities, including psychiatric disorders. This study aimed to identify factors influencing anxiety, depression, and quality of life (QoL) in patients with psoriasis. Methods: This observational study included 112 patients diagnosed with psoriasis. Dermatological and psychiatric assessments were conducted using Psodisk, the Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Symptom Checklist-90-Revised (SCL-90-R), and 36-Item Short Form Health Survey (SF-36). Descriptive statistics, correlation analyses, and multivariate regression models were employed. Results: The sample was predominantly middle-aged males (mean age 48.91 years). Females (p < 0.001), patients with arthritis (p < 0.05), and those with a sedentary lifestyle (p < 0.05) showed higher anxiety and depression scores. Psodisk subscales significantly correlated with psychiatric symptoms and QoL measures (p < 0.001). Pain (B: 0.63, p < 0.05; B: −2.03, p < 0.01) and sleep disturbances (B: 0.68, p < 0.01; B: 0.60, p < 0.01; B: −1.46, p < 0.01; B: −1.57, p < 0.05; B: 3.91, p < 0.05) emerged as major predictors of poor mental health and reduced QoL. Conclusions. The study underscores the complex relationship between psoriasis, psychiatric comorbidities, and QoL. Key factors exacerbating anxiety and depression include female gender, arthritis, and sedentary lifestyle. Comprehensive management of psoriasis should address both dermatological and psychological aspects, with a focus on pain relief and improving sleep quality to enhance overall patient well-being.

Virtual reality (VR) applications in paediatric rehabilitation are recent but promising. This brief report describes a VR rehabilitation program for a small sample of children with Developmental Coordination Disorder (DCD). The program focused explicitly on executive functions, a key area of concern for this population. It was conducted over 11 weeks in the CARE Lab. This lab was designed with appropriate structural characteristics and sophisticated technology to provide a rehabilitative setting with recreational and semi-immersive features. Before and after the VR training, the children were evaluated in terms of visual attention, inhibition, planning abilities, and visual–motor coordination. The rehabilitation programs were customised according to the clinical needs and the functional profile of each patient, proposing different games with variable complexity levels. These preliminary results showed a global and clinically significant change in executive functions, especially visual attention and inhibition skills. These findings suggest interesting implications for clinical practice, providing new information for professionals regarding the application of VR in the field of paediatric rehabilitation.

(1) Background: Vulvodynia is characterized by vulvar pain for at least three months and may have related variables, one of these being pelvic floor hypertonus. The purpose of this study was to compare the therapeutic effectiveness of two weekly sessions of pelvic floor rehabilitation and 5 mg of vaginal diazepam daily vs. pelvic floor rehabilitation alone in individuals with vulvodynia. (2) Methods: A single-center, not-blind, randomized study enrolled 20 vulvodynic patients: A total of 10 were treated with dual therapy (intravaginal diazepam and pelvic floor rehabilitation), and 10 were treated with only pelvic floor rehabilitation. All of them underwent a pelvic floor ultrasound examination and VAS pain and Marinoff scale assessments before the beginning of therapy as well as three and six months later. (3) Results: The elevator plate angle ranged from 8.2 to 9.55 (p = 0.0005), hiatal area diameter ranged from 1.277 to 1.482 (p = 0.0002), levator symphysis distance ranged from 3.88 to 4.098 (p = 0.006), anorectal angle ranged from 121.9 to 125.49 (p = 0.006), Marinoff scale ranged from 2.3 to 1.4 (p = 0.009), and VAS scale ranged from 5.8 to 2.8 (p < 0.001). (4) Conclusions: This pilot study demonstrates that the suggested treatment improves the hypertonicity of the pelvic floor, as measured by ultrasound parameters, correlating with a reduction in symptomatology.

ABSTRACT: Objectives: Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) resistant to ceftazidime/avibactam (CZA) and susceptible to meropenem (MEM). Although susceptible to MEM in vitro, the possibility of developing MEM resistance overtime is a concern. We describe the clinical characteristics of patients with colonization/infection due to KPC variants with a focus on the in vitro activity of fosfomycin (FOS)-containing combinations. Methods: Patients with colonization/infection due to a KPC variant were included. Fosfomycin susceptibility was performed by agar dilution method. Synergistic activity of FOS-based combinations was evaluated by gradient strip-agar diffusion method. The emergence of in vitro MEM resistance was also tested. Results: Eleven patients were included: eight with infection [four with ventilator-associated pneumonia and four with bloodstream infections] and three with colonization. Previous therapy with CZA was administered to all patients (with a mean cumulative duration of 23 days). All subjects with infection received meropenem, in monotherapy (n = 4) or with amikacin (n = 2) or fosfomycin (n = 2), and achieved clinical cure. A new CZA-susceptible and MEM-resistant KPC-Kp strain was subsequently isolated in three patients (27.3%). Meropenem/vaborbactam (MVB) showed high in vitro activity, while FOS+MEM combination was synergistic in 40% of cases. In vitro resistance to MEM was observed with maintenance of CZA resistance. Conclusions: Detection of KPC variants may occur within the same patient, especially if CZA has been previously administered. Although clinical success has been obtained with carbapenems, the emergence of MEM resistance is a concern. Fosfomycin plus meropenem is synergistic and may be a valuable combination option for KPC variants, while MVB may be considered in monotherapy. The detection of KPC variants in an endemic setting for KPC-Kp represents a worryingly emerging condition. The optimal therapeutic approach is still unknown and the development of meropenem resistance is of concern, which may lead to therapeutic failure in clinical practice. In these cases, the addition of fosfomycin to meropenem, or a more potent antibiotic, such as meropenem/vaborbactam, may be valuable therapeutic options.

This Letter reports the first observation of the onset of fully developed turbulence in the solar corona. Long time series of white-light coronal images, acquired by Metis aboard Solar Orbiter at 2 minutes cadence and spanning about 10 hr, were studied to gain insight into the statistical properties of fluctuations in the density of the coronal plasma in the time domain. From pixel-by-pixel spectral frequency analysis in the whole Metis field of view, the scaling exponents of plasma fluctuations were derived. The results show that, over timescales ranging from 1 to 10 hr and corresponding to the photospheric mesogranulation-driven dynamics, the density spectra become shallower moving away from the Sun, resembling a Kolmogorov-like spectrum at 3 R _⊙ . According to the latest observation and interpretive work, the observed 5/3 scaling law for density fluctuations is indicative of the onset of fully developed turbulence in the corona. Metis observation-based evidence for a Kolmogorov turbulent form of the fluctuating density spectrum casts light on the evolution of 2D turbulence in the early stages of its upward transport from the low corona.

Abstract The clinical use of lung ultrasound (LUS) has made more efficient many diagnostic processes at bedside. The great power of LUS is a superior diagnostic sensitivity in many applications, when compared to chest radiography (CXR). The implementation of LUS in emergency is contributing to reveal a growing number of radio-occult pulmonary conditions. In some diseases, the superior sensitivity of LUS is a great advantage, like for pneumothorax and pulmonary edema. Diagnosing at bedside pneumothoraxes, pulmonary congestions, and COVID-19 pneumonia that are visible by LUS but undetected by CXR may be decisive for appropriate management, and even for saving lives. However, in other conditions, like bacterial pneumonia and small peripheral infarctions due to subsegmental pulmonary embolism, the high sensitivity of LUS does not always lead to advantages. Indeed, we doubt that it is always necessary to treat by antibiotics patients suspected of lower respiratory tract infection, who show radio-occult pulmonary consolidations, and to treat by anticoagulation patients with small subsegmental pulmonary embolism. The possibility that we are overtreating radio-occult conditions should be investigated with dedicated clinical trials.

Abstract Although the discovery of the critical role of α-synuclein (α-syn) in the pathogenesis of Parkinson’s disease (PD) is now twenty-five years old, it still represents a milestone in PD research. Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, α-syn-dependent early synaptic and plastic alterations and the underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, the presence of early inflammation in experimental models and PD patients, occurring before deposition and spreading of α-syn, suggests a mechanistic link between inflammation and synaptic dysfunction. The knowledge of these early mechanisms is of seminal importance to support the research on reliable biomarkers to precociously identify the disease and possible disease-modifying therapies targeting α-syn. In this review, we will discuss these critical issues, providing a state of the art of the role of this protein in early PD and other synucleinopathies.

Background and Objectives: Medical students represent the ideal target group for promoting mental health and mental wellbeing, being exposed to specific risk factors, such as the content of medical training, the exposure to sickness and death, and a stressful academic routine. Medical students report high levels of cynicism and emotional exhaustion, which represent two of the essential features of burnout syndrome. In this systematic review, studies assessing the levels of burnout among medical students through validated tools worldwide were analyzed. Materials and Methods: A systematic review has been performed in order to identify studies: (1) focusing on samples of medical students; (2) evaluating burnout syndrome using validated tools; (3) providing prevalence data on burnout; and (4) written in English. Results: Out of the 5547 papers initially obtained, 64 were finally included in the analysis. The sample sizes ranged from 51 to 2682 participants. Almost all studies had a cross-sectional design; the Maslach Burnout Inventory and its related versions were the most frequently used assessment tools. The prevalence of burnout, which was stratified based on gender and academic stage, ranged from 5.6 to 88%. Burnout was mostly predicted by thoughts of stopping medical education, negative life events, lack of support, dissatisfaction, and poor motivation. Conclusions: The prevalence of burnout syndrome in medical students is quite heterogeneous, reaching a peak of 88% in some countries. However, several predictors have been identified, including negative life events or poor motivation. These findings highlight the need to develop preventive interventions targeting the future generation of medical doctors, in order to improve their coping strategies and resilience styles.

In Parkinson's disease (PD), post-mortem studies in affected brain regions have demonstrated a decline in mitochondrial number and function. This combined with many studies in cell and animal models suggest that mitochondrial dysfunction is central to PD pathology. We and others have shown that the mitochondrial protein deacetylase, SIRT3, has neurorestorative effects in PD models. In this study, to determine whether there is a link between PD pathology and SIRT3, we analysed SIRT3 levels in human subjects with PD, and compared to age-matched controls. In the SNc of PD subjects, SIRT3 was reduced by 56.8 ± 15.5% compared to control, regardless of age (p

Abstract Background The present study aims to assess clinical and psychological correlates of psychological functioning in patients with mood disorders, in a naturalistic setting. In particular, we aimed to describe which sociodemographic, clinical, and temperamental dispositions are more frequently associated with poor psychological functioning, and to describe the association between cognitive and psychological functioning in euthymic patients with major depression and bipolar disorder. Methods Inclusion criteria were as follows: (1) diagnosis of major depression, or bipolar disorder type I or II; (2) age between 18 and 65 years; and (3) being in a stable phase of the disorder. Patients’ psychiatric symptoms, quality of life, affective temperaments, and impulsivity were investigated with validated assessment instruments. Results 166 patients have been recruited, mainly female (55.4%), whose mean age was 47.1 ± 14.2 years. 42.6% of individuals reported a diagnosis of major depression. According to regression analyses, poor cognitive performance (p

Abstract Background The incidence of the highly morbid and potentially lethal gangrenous cholecystitis was reportedly increased during the COVID-19 pandemic. The aim of the ChoCO-W study was to compare the clinical findings and outcomes of acute cholecystitis in patients who had COVID-19 disease with those who did not. Methods Data were prospectively collected over 6 months (October 1, 2020, to April 30, 2021) with 1-month follow-up. In October 2020, Delta variant of SARS CoV-2 was isolated for the first time. Demographic and clinical data were analyzed and reported according to the STROBE guidelines. Baseline characteristics and clinical outcomes of patients who had COVID-19 were compared with those who did not. Results A total of 2893 patients, from 42 countries, 218 centers, involved, with a median age of 61.3 (SD: 17.39) years were prospectively enrolled in this study; 1481 (51%) patients were males. One hundred and eighty (6.9%) patients were COVID-19 positive, while 2412 (93.1%) were negative. Concomitant preexisting diseases including cardiovascular diseases (p

Background: Hemangiomas are aberrant proliferations of blood vessels and the most frequent benign pediatric soft tissue tumors. Although they are common, genital localization is rare. This study aimed to assist doctors in the diagnosis, management, and treatment of pediatric vulvovaginal hemangiomas by conducting a review of the literature. Methods: We conducted a literature review including papers published between August 2009 and May 2023. Results: While most hemangiomas are usually indolent and resolve with time, in some cases, especially cervicovaginal and uterine ones, they might present with severe symptoms like heavy bleeding and need further instrumental investigation for diagnosis, like CT or MRI. As for the treatment, many options are available, with medical therapy or expectant management being the first choice. Conclusions: Vulvovaginal pediatric hemangiomas are rare and require more research on how to detect and manage these lesions, especially the symptomatic and the psychologically impacting ones. For the time being, treatment should be personalized based on the patient’s situation and clinician’s expertise.

In this paper, we prove an existence and uniqueness result for a class of Dirichlet boundary value problems whose model is −Δpu=β|∇u|q+c|u|p−2u+fin Ω,u=0on ∂Ω, where Ω is an open bounded subset of RN, N≥2, 1

Abstract Background Lung ultrasound (LUS) has a role in the diagnosis of pulmonary embolism (PE) mainly based on the visualization of pulmonary infarctions. However, examining the whole chest to detect small peripheral infarctions by LUS may be challenging. Pleuritic pain, a frequent presenting symptom in patients with PE, is usually localized in a restricted chest area identified by the patient itself. Our hypothesis is that sensitivity of LUS for PE in patients with pleuritic chest pain may be higher due to the possibility of focusing the examination in the painful area. We combined data from three prospective studies on LUS in patients suspected of PE and extracted data regarding patients with and without pleuritic pain at presentation to compare the performances of LUS. Results Out of 872 patients suspected of PE, 217 (24.9%) presented with pleuritic pain and 279 patients (32%) were diagnosed with PE. Pooled sensitivity of LUS for PE in patients with and without pleuritic chest pain was 81.5% (95% CI 70–90.1%) and 49.5% (95% CI 42.7–56.4%) (p

Abstract Objectives The purpose of this study is to provide expert consensus recommendations to establish a global ultrasound curriculum for undergraduate medical students. Methods 64 multi-disciplinary ultrasound experts from 16 countries, 50 multi-disciplinary ultrasound consultants, and 21 medical students and residents contributed to these recommendations. A modified Delphi consensus method was used that included a systematic literature search, evaluation of the quality of literature by the GRADE system, and the RAND appropriateness method for panel judgment and consensus decisions. The process included four in-person international discussion sessions and two rounds of online voting. Results A total of 332 consensus conference statements in four curricular domains were considered: (1) curricular scope (4 statements), (2) curricular rationale (10 statements), (3) curricular characteristics (14 statements), and (4) curricular content (304 statements). Of these 332 statements, 145 were recommended, 126 were strongly recommended, and 61 were not recommended. Important aspects of an undergraduate ultrasound curriculum identified include curricular integration across the basic and clinical sciences and a competency and entrustable professional activity-based model. The curriculum should form the foundation of a life-long continuum of ultrasound education that prepares students for advanced training and patient care. In addition, the curriculum should complement and support the medical school curriculum as a whole with enhanced understanding of anatomy, physiology, pathophysiological processes and clinical practice without displacing other important undergraduate learning. The content of the curriculum should be appropriate for the medical student level of training, evidence and expert opinion based, and include ongoing collaborative research and development to ensure optimum educational value and patient care. Conclusions The international consensus conference has provided the first comprehensive document of recommendations for a basic ultrasound curriculum. The document reflects the opinion of a diverse and representative group of international expert ultrasound practitioners, educators, and learners. These recommendations can standardize undergraduate medical student ultrasound education while serving as a basis for additional research in medical education and the application of ultrasound in clinical practice.

Abstract Background The effects of lockdown on non‐COVID patients are varied and unexpected. The aim is to evaluate the burden of cardiac arrhythmias during a lockdown period because of COVID‐19 pandemics in a population implanted with cardiac defibrillators and followed by remote monitoring. Methods In this retrospective, multicentre cohort study, we included 574 remotely monitored implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy‐defibrillator (CRT‐D) recipients implanted before January 1, 2019, at seven hospitals in the Campania region, comparing the burden of arrhythmias occurred during the lockdown period because of COVID‐19 epidemics (from March 9 to May 1, 2020) with the arrhythmias burden of the corresponding period in 2019 (reference period). Data collection was performed through remote monitoring. Results During the lockdown period, we observed ventricular tachyarrhythmias (ventricular tachycardia or fibrillation) in 25 (4.8%) patients while in seasonal reference period we documented ventricular tachyarrhythmias in 12 (2.3%) patients; the comparison between the periods is statistically significant (P

BackgroundThe introduction of electronic workflows has allowed for the flow of raw uncontextualized clinical data into medical documentation. As a result, many electronic notes have become replete of “noise” and deplete clinically significant “signals.” There is an urgent need to develop and implement innovative approaches in electronic clinical documentation that improve note quality and reduce unnecessary bloating. ObjectiveThis study aims to describe the development and impact of a novel set of templates designed to change the flow of information in medical documentation. MethodsThis is a multihospital nonrandomized prospective improvement study conducted on the inpatient general internal medicine service across 3 hospital campuses at the New York University Langone Health System. A group of physician leaders representing each campus met biweekly for 6 months. The output of these meetings included (1) a conceptualization of the note bloat problem as a dysfunction in information flow, (2) a set of guiding principles for organizational documentation improvement, (3) the design and build of novel electronic templates that reduced the flow of extraneous information into provider notes by providing link outs to best practice data visualizations, and (4) a documentation improvement curriculum for inpatient medicine providers. Prior to go-live, pragmatic usability testing was performed with the new progress note template, and the overall user experience was measured using the System Usability Scale (SUS). Primary outcome measures after go-live include template utilization rate and note length in characters. ResultsIn usability testing among 22 medicine providers, the new progress note template averaged a usability score of 90.6 out of 100 on the SUS. A total of 77% (17/22) of providers strongly agreed that the new template was easy to use, and 64% (14/22) strongly agreed that they would like to use the template frequently. In the 3 months after template implementation, general internal medicine providers wrote 67% (51,431/76,647) of all inpatient notes with the new templates. During this period, the organization saw a 46% (2768/6191), 47% (3505/7819), and 32% (3427/11,226) reduction in note length for general medicine progress notes, consults, and history and physical notes, respectively, when compared to a baseline measurement period prior to interventions. ConclusionsA bundled intervention that included the deployment of novel templates for inpatient general medicine providers significantly reduced average note length on the clinical service. Templates designed to reduce the flow of extraneous information into provider notes performed well during usability testing, and these templates were rapidly adopted across all hospital campuses. Further research is needed to assess the impact of novel templates on note quality, provider efficiency, and patient outcomes.

Background: In recent years, several interesting case reports have been published which describe the possible role of SARS-CoV-2 infection or vaccination in the etiopathogenesis of Lipschütz ulcer. Our aim is to analyze this association and provide a rapid algorithm that is of support to gynecologists and dermatologists both in the diagnosis and in setting up the therapy. To do so, in this paper, we describe an interesting case of acute vulvar ulcer triggered by SARS-CoV-2 infection and review the related literature. Methods: We conducted a literature review including papers published between October 2021 and April 2023, and we described the case of a patient referred to our clinic with Lipschütz ulcer and SARS-CoV-2 infection. Results: In almost all cases analyzed, a correlation with SARS-CoV-2 infection or vaccination was found; ulcers usually manifest after 2 to 4 weeks and are associated with flu-like symptoms. A concordance in review papers, as well as in our case report, was also found about the treatment, which is mainly symptomatic. Conclusions: Previous infection or vaccination for SARS-CoV-2 should be included as possible etiopathogenetic factors in the onset of Lipschütz ulcer.

Abstract Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.

This Letter reports the first observational estimate of the heating rate in the slowly expanding solar corona. The analysis exploits the simultaneous remote and local observations of the same coronal plasma volume, with the Solar Orbiter/Metis and the Parker Solar Probe instruments, respectively, and relies on the basic solar wind magnetohydrodynamic equations. As expected, energy losses are a minor fraction of the solar wind energy flux, since most of the energy dissipation that feeds the heating and acceleration of the coronal flow occurs much closer to the Sun than the heights probed in the present study, which range from 6.3 to 13.3 R _⊙ . The energy deposited to the supersonic wind is then used to explain the observed slight residual wind acceleration and to maintain the plasma in a nonadiabatic state. As derived in the Wentzel–Kramers–Brillouin limit, the present energy transfer rate estimates provide a lower limit, which can be very useful in refining the turbulence-based modeling of coronal heating and subsequent solar wind acceleration.

BackgroundMain aims of the present paper are to: (1) assess the prevalence of antenatal depression (AD) and identify its predictors; (2) analyse the impact of AD on obstetric outcomes and on the incidence of post-partum depression.MethodsAll pregnant women referring to the Gynecology and Obstetrics inpatients unit of the University of Campania “Luigi Vanvitelli” were invited to participate. Upon acceptance, women completed the Italian version of the Edinburgh Postnatal Depression Scale and an ad-hoc questionnaire on the women's sociodemographic, gynecological and peripartum characteristics as well as their psychiatric history. Women were assessed at each trimester of pregnancy, immediately after the childbirth and after one, three, 6 and 11 months.Results268 pregnant women were recruited, with a mean of 32.2 (±5.81) years. Ninety-seven women (36.2%) reported the presence of depressive symptoms during pregnancy. Predictors of AD were personal history of depression, a family history for depressive disorders and problematic relationships with the partner. The presence of AD was associated to a reduced gestational age at the time of delivery, a lower APGAR score at 1 and 5 min, labor induction and admission of the new-born into neonatal intensive care unit. Mothers with antenatal depression are less likely to natural breastfeed. Lastly, antenatal depression was a risk factor for higher EPDS scores at follow-ups.ConclusionsOur results support the idea that women should be screened during pregnancy and post-partum for the presence of depressive and anxiety symptoms. Health professionals should be adequately trained to detect psychiatric symptoms during pregnancy.

Abstract Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

Stockdale et al. assess longitudinal faecal virome changes in a rat model of Parkinson’s Disease (PD) in which either monomeric or preformed fibrils (PFF) of α-synuclein were administered directly into their enteric nervous system. They demonstrate that virome alterations are potentially reactive to host α-synuclein changes that are associated with PD development.

Introduction and aims: The limited therapeutic options for ischemic stroke treatment render necessary the identification of new strategies. In recent years, it has been shown that natural compounds may represent a valid therapeutic opportunity. Therefore, the present study aimed to evaluate the protective effect of Ruta graveolens water extract (RGWE) in an in vivo experimental model of brain ischemia. Methods: RGWE effects on ischemic damage and neurological function were evaluated in adult rats subjected to transient occlusion of the Middle Cerebral Artery (tMCAO), receiving two intraperitoneal injections of RGWE, 100 and 300 min after the induction of ischemia. In addition, astroglial and microglial activation was measured as GFAP and IBA-1 expression by immunofluorescence and confocal microscopy analysis. Results: Treatment with RGWE containing 10 mg/kg of Rutin, the major component, ameliorates the ischemic damage and improves neurological performances. Interestingly, the pro-inflammatory states of astrocytes and microglia, respectively detected by using C3 and iNOS markers, were significantly reduced in ipsilateral cortical and striatal areas in ischemic RGWE-treated rats. Conclusions: RGWE shows a neuroprotective effect on brain infarct volume extent in a transient focal cerebral ischemia model and this effect was paralleled by the prevention of pro-inflammatory astroglial and microglial activation. Collectively, our findings support the idea that natural compounds may represent potential therapeutic opportunities against ischemic stroke.

Greater than moderate alcohol use spans a continuum that includes high levels of total alcohol consumed per period (heavy drinking) as well as episodes of intense drinking (binges) and can give rise to alcohol use disorder (AUD) when associated with an inability to control alcohol use despite negative consequences. Although moderate drinking and AUD have standard, operable definitions in the United States (US), a significant “gray area” remains in which an individual may exceed recommended drinking guidelines but does not meet the criteria for AUD (hereafter referred to as unhealthy alcohol use). To address this need, we conducted a structured literature search to evaluate how this gray area is defined and assess its burden within the US. For purposes of this review, we will refer to this gray area as “unhealthy alcohol use.” Although numerous terms are used to describe various unsafe drinking practices, our review did not find any studies in which the specific prevalence and/or burden of unhealthy alcohol use was evaluated. That is, we found no studies that focus exclusively on individuals who exceed moderate drinking guidelines but do not meet AUD criteria. Furthermore, we did not discover an established framework for identifying individuals with unhealthy alcohol use. The lack of a consistent framework for identifying unhealthy alcohol users has significant implications for patient management and disease burden assessment. Therefore, we propose the following framework in which unhealthy alcohol use comprises 2 distinct subpopulations: those at risk of experiencing alcohol-related consequences and those who have subthreshold problems associated with use. The former, termed “risky drinkers,” are defined by exceeding recommended guidelines for moderate drinking (⩽1 or 2 drinks per day for women and men, respectively). People with subthreshold problems associated with use, defined as exhibiting exactly 1 AUD symptom, would be classified as “problematic drinkers” within this proposed framework. These definitions would help bring the core elements of unhealthy alcohol use into focus, which in turn would help identify and provide management strategies sooner to those affected and reduce the overall burden of unhealthy alcohol use.

Abstract Lung ultrasound (LUS) is a promising point-of-care imaging technology for diagnosing and managing pneumonia. We sought to explore serial LUS examinations in children with chest-indrawing pneumonia in resource-constrained settings and compare their clinical and LUS imaging courses longitudinally. We conducted a prospective, observational study among children aged 2 through 23 months with World Health Organization Integrated Management of Childhood Illness chest-indrawing pneumonia and among children without fast breathing, chest indrawing or fever (no pneumonia cohort) at 2 district hospitals in Mozambique and Pakistan. We assessed serial LUS at enrollment, 2, 6, and 14 days, and performed a secondary analysis of enrolled children’s longitudinal clinical and imaging courses. By Day 14, the majority of children with chest-indrawing pneumonia and consolidation on enrollment LUS showed improvement on follow-up LUS (100% in Mozambique, 85.4% in Pakistan) and were clinically cured (100% in Mozambique, 78.0% in Pakistan). In our cohort of children with chest-indrawing pneumonia, LUS imaging often reflected the clinical course; however, it is unclear how serial LUS would inform the routine management of non-severe chest-indrawing pneumonia.

Abstract Background During COVID-19 pandemic, optimization of the diagnostic resources is essential. Lung Ultrasound (LUS) is a rapid, easy-to-perform, low cost tool which allows bedside investigation of patients with COVID-19 pneumonia. We aimed to investigate the typical ultrasound patterns of COVID-19 pneumonia and their evolution at different stages of the disease. Methods We performed LUS in twenty-eight consecutive COVID-19 patients at both admission to and discharge from one of the Padua University Hospital Intensive Care Units (ICU). LUS was performed using a low frequency probe on six different areas per each hemithorax. A specific pattern for each area was assigned, depending on the prevalence of A-lines (A), non-coalescent B-lines (B1), coalescent B-lines (B2), consolidations (C). A LUS score (LUSS) was calculated after assigning to each area a defined pattern. Results Out of 28 patients, 18 survived, were stabilized and then referred to other units. The prevalence of C pattern was 58.9% on admission and 61.3% at discharge. Type B2 (19.3%) and B1 (6.5%) patterns were found in 25.8% of the videos recorded on admission and 27.1% (17.3% B2; 9.8% B1) on discharge. The A pattern was prevalent in the anterosuperior regions and was present in 15.2% of videos on admission and 11.6% at discharge. The median LUSS on admission was 27.5 [21–32.25], while on discharge was 31 [17.5–32.75] and 30.5 [27–32.75] in respectively survived and non-survived patients. On admission the median LUSS was equally distributed on the right hemithorax (13; 10.75–16) and the left hemithorax (15; 10.75–17). Conclusions LUS collected in COVID-19 patients with acute respiratory failure at ICU admission and discharge appears to be characterized by predominantly lateral and posterior non-translobar C pattern and B2 pattern. The calculated LUSS remained elevated at discharge without significant difference from admission in both groups of survived and non-survived patients.

Abstract Background Lung ultrasound (LUS) and chest radiography (CXR) are the most used chest imaging tools in the early diagnosis of COVID-19 associated pneumonia. However, the relationship between LUS and CXR is not clearly defined. The aim of our study was to describe the comparison between LUS interpretation and CXR readings in the first approach to patients suspected of COVID-19. Methods In the time of the first COVID-19 pandemic surge, we prospectively evaluated adult patients presenting to an emergency department complaining of symptoms raising suspicion of COVID-19. Patients were studied by LUS and only those performing also CXR were analyzed. All the patients performed viral reverse transcriptase-polymerase chain reaction (RT-PCR). LUS studies were classified in 4 categories of probabilities, based on the presence of typical or alternative signs of COVID-19-associated interstitial pneumonia. Accordingly, the CXR readings were retrospectively adapted by 2 experts in 4 categories following the standard language that describes the computed tomography (CT) findings. Patients were divided in two groups, based on the agreement of the LUS and CXR categories. Results were also compared to RT-PCR and, when available, to CT studies. Results We analyzed 139 cases (55 women, mean age 59.1 ± 15.5 years old). The LUS vs CXR results disagreed in 60 (43.2%) cases. RT-PCR was positive in 88 (63.3%) cases. In 45 cases, a CT scan was also performed and only 4 disagreed with LUS interpretation versus 24 in the comparison between CT and CXR. In 18 cases, LUS detected signs of COVID-19 pneumonia (high and intermediate probabilities) while CXR reading was negative; in 14 of these cases, a CT scan or a RT-PCR-positive result confirmed the LUS interpretation. In 6 cases, LUS detected signs of alternative diagnoses to COVID-19 pneumonia while CXR was negative; in 4 of these cases, CT scan confirmed atypical findings. Conclusion Our study demonstrated a strong disagreement between LUS interpretation and CXR reading in the early approach to patients suspected of COVID-19. Comparison with CT studies and RT-PCR results seems to confirm the superiority of LUS over a second retrospective reading of CXR.

Abstract Critical care ultrasound (CCUS) is an essential component of intensive care practice. Although existing international guidelines have focused on training principles and determining competency in CCUS, few countries have managed to operationalize this guidance into an accessible, well-structured programme for clinicians training in multidisciplinary intensive care. We seek to update and reaffirm appropriate CCUS scope so that it may be integrated into the international Competency-based Training in Intensive Care Medicine. The resulting recommendations offer the most contemporary and evolved set of core CCUS competencies for an intensive care clinician yet described. Importantly, we discuss the rationale for inclusion but also exclusion of competencies listed. Background/aim Critical care ultrasound (CCUS) is an essential component of intensive care practice. The purpose of this consensus document is to determine those CCUS competencies that should be a mandatory part of training in multidisciplinary intensive care. Methods A three-round Delphi method followed by face-to-face meeting among 32 CCUS experts nominated by the European Society of Intensive Care Medicine. Agreement of at least 90% of experts was needed in order to enlist a competency as mandatory. Results The final list of competencies includes 15 echocardiographic, 5 thoracic, 4 abdominal, deep vein thrombosis diagnosis and central venous access aid. Conclusion The resulting recommendations offer the most contemporary and evolved set of core CCUS competencies for an intensive care clinician yet described.

Abstract Background Pulmonary atelectasis in anesthetized children is easily reverted by lung recruitment maneuvers. However, the high airways pressure reached during the maneuver could negatively affect hemodynamics. The aim of this study is to assess the effect and feasibility of a postural lung recruitment maneuver (P-RM); i.e., a new maneuver that opens up the atelectatic lung areas based on changing the child’s body position under constant ventilation with moderated driving pressure (12 cmH2O) and of positive end-expiratory pressure (PEEP, 10 cmH2O). Forty ASA I–II children, aged 6 months to 7 years, subjected to general anesthesia were studied. Patients were ventilated with volume control mode using standard settings with 5 cmH2O of PEEP. They were randomized into two groups: (1) control group (C group, n = 20)—ventilation was turned to pressure control ventilation using a fixed driving pressure of 12 cmH2O. PEEP was increased from 5 to 10 cmH2O during 3 min maintaining the supine position. (2) P-RM group (n = 20)—patients received the same increase in driving pressure and PEEP, but they were placed, respectively, in the left lateral position, in the right lateral position (90 s each), and back again into the supine position after 3 min. Then, ventilation returned to baseline settings in volume control mode. Lung ultrasound-derived aeration score and respiratory compliance were assessed before (T1) and after (T2) 10 cmH2O of PEEP was applied. Results At baseline ventilation (T1), both groups showed similar aeration score (P-RM group 9.9 ± 1.9 vs C group 10.4 ± 1.9; p = 0.463) and respiratory compliance (P-RM group 15 ± 6 vs C group 14 ± 6 mL/cmH2O; p = 0.517). At T2, the aeration score decreased in the P-RM group (1.5 ± 1.6 vs 9.9 ± 2.1; p

Abstract The two main pathological hallmarks of Parkinson’s disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson’s disease (Olanow, Mov Disord 34:812–815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54–63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that α-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic α-synuclein, such as mechanisms that increase endogenous α-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in α-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic α-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.

Endothelial dysfunction (ED) causes worse prognoses in heart failure (HF) patients treated with cardiac resynchronization therapy (CRTd). ED triggers the downregulation of microRNA-130 (miR-130a-5p), which targets endothelin-1 (ET-1). Thus, we evaluated ED and the response to CRTd by assessing miR-130a-5p and ET-1 serum levels. We designed a prospective multi-center study with a 1-year follow-up to evaluate ED, ET-1, and miR-130a-5p in CRTd patients with ED (ED-CRTd) vs. patients without ED (NED-CRTd). Clinical outcomes were CRTd response, HF hospitalization, cardiac death, and all-cause death. At 1-year follow-up, NED-CRTd (n = 541) vs. ED-CRTd (n = 326) patients showed better clinical statuses, lower serum values of B type natriuretic peptide (BNP: 266.25 ± 10.8 vs. 297.43 ± 16.22 pg/mL; p < 0.05) and ET-1 (4.57 ± 0.17 vs. 5.41 ± 0.24 pmol/L; p < 0.05), and higher values of miR-130a-5p (0.51 ± 0.029 vs. 0.41 ± 0.034 A.U; p < 0.05). Compared with NED-CRTd patients, ED-CRTd patients were less likely to be CRTd responders (189 (58%) vs. 380 (70.2%); p < 0.05) and had higher rates of HF hospitalization (115 (35.3%) vs. 154 (28.5%); p < 0.05) and cardiac deaths (30 (9.2%) vs. 21 (3.9%); p < 0.05). Higher miR-130a-5p levels (HR 1.490, CI 95% [1.014–2.188]) significantly predicted CRTd response; the presence of hypertension (HR 0.818, CI 95% [0.669–0.999]), and displaying higher levels of ET-1 (HR 0.859, CI 98% [0.839–0.979]), lymphocytes (HR 0.820, CI 95% [0.758–0.987]), LVEF (HR 0.876, CI 95% [0.760–0.992]), and ED (HR 0.751, CI 95% [0.624–0.905]) predicted CRTd non-response. Higher serum miR-130a-5p levels (HR 0.332, CI 95% [0.347–0.804]) and use of ARNI (HR 0.319, CI 95% [0.310–0.572]) predicted lower risk of HF hospitalization, whereas hypertension (HR 1.818, CI 95% [1.720–2.907]), higher BNP levels (HR 1.210, CI 95% [1.000–1.401]), and presence of ED (HR 1.905, CI 95% [1.238–2.241]) predicted a higher risk of HF hospitalization. Hence, serum miR-130a-5p could identify different stages of ED and independently predict CRTd response, therefore representing a novel prognostic HF biomarker.