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Coronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy. The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome. This observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24.sup.th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HR.sub.OW). Overall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO.sub.2 /FiO.sub.2 200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n = 29, 22.3%), methylprednisolone (n = 45, 34.6%), or both (n = 56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HR.sub.OW 0.48, 95%CI, 0.23-0.99; p = 0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HR.sub.OW 0.41, 95%CI: 0.19-0.89, p = 0.025. Early adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.

Background/Objectives: Early experiences can significantly influence brain development, particularly when they occur during specific time windows known as sensitive or critical periods. Therefore, the early promotion of neurodevelopmental functions is crucial in children at risk for neurodevelopmental disabilities, such as those with cerebral palsy. This article introduces AMIRA (A Multidimensional and Integrated Rehabilitation Approach), a rehabilitative framework designed for infants at risk of neurodevelopmental disabilities. Methods: AMIRA is intended to guide clinical–rehabilitation reasoning rather than prescribe a rigid sequence of predetermined activities for the child. The theoretical foundation and structure of AMIRA are presented by formalizing its criteria, objectives, tools, and intervention procedures. The framework comprises four distinct sections, each supported by adaptive strategies to facilitate access to materials and to promote play-based interactions among the child, their environment, and communication partners. Particular attention is given to optimizing both micro- and macro-environments for children with, or at risk of, co-occurring visual impairment. Each rehabilitative section includes three progressive phases: an initial observation phase, a facilitation phase to support the child’s engagement, and an active experimentation phase that gradually introduces more challenging tasks. Results: The intervention pathways in AMIRA are organized according to six core developmental domains: behavioral–emotional self-regulation, visual function, postural–motor skills, praxis, interaction and communication, and cognitive function. These are outlined in structured charts that serve as flexible guidelines rather than prescriptive protocols. Each chart presents activities of increasing complexity aligned with typical developmental milestones up to 24 months of age. For each specific ability, the corresponding habilitation goals, contextual recommendations (including environmental setup, objects, and tools), and suggested activities are provided. Conclusions: This study presents a detailed intervention approach, offering both a practical framework and a structured set of activities for use in rehabilitative settings. Further studies will explore the efficacy of the proposed standardized approach.

Background: Cerebral Visual Impairment (CVI) is a very common finding in children affected by Cerebral Palsy (CP). In this paper we studied the characteristics of CVI of a large group of children with CP and CVI, describing their neurovisual profiles according to three different age subgroups (subgroup 1: infants 6 months-2 years; subgroup 2: pre-school age 3-5 years; subgroup 3: school age ≥ 6 years). Methods: we enrolled 180 subjects (104 males, mean age 66 ± 42.6 months; range 6-192 months) with CP and CVI for the study. We carried out a demographic and clinical data collection, neurological examination, developmental or cognitive assessment, and a video-recorded visual function assessment an evaluation of ophthalmological characteristics, oculomotor functions, and basic visual functions. In school-aged children, we also performed an evaluation of a their cognitive-visual profiles. Results: There were signs of CVI in all the three subgroups. Subgroup 1 (62 children) and subgroup 2 (50 children) were different for fixation (p=0.02), visual acuity (p=0.03) and contrast sensitivity (p<0.01), being more frequently impaired in younger children. Comparing subgroup 2 with subgroup 3 (68 children), the older children presented more frequently myopia (p=0.02) esotropia (p=0.02) and alteration in smooth pursuit (p=0.03) and saccades (p<0.01). Furthermore, fixation, smooth pursuit, visual acuity, contrast sensitivity and visual filed (p<0.01) were more frequently impaired in younger children (subgroup 1) compared to the older ones. Multiple correspondence analysis confirmed the different neurovisual profiles according to age: younger children with CP showed more signs of CVI compared to the older ones. 34 out of 68 children belonging to subgroup 3 underwent the cognitive visual evaluation; an impairment of cognitive visual skills was detected in 21 subjects. Conclusions: Younger children with CP showed more signs of CVI compared to the older ones, likely for the physiological maturation of visual system and mechanisms of neuroplasticity. In this direction, we suggest an early neurovisual evaluation to detect any weak visual functions

The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56 bright CD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56 dim CD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1 bright CXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1 bright CXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches.

Background The prevalence of kidney involvement during SARS-CoV-2 infection has been reported to be high. Nevertheless, data are lacking about the determinants of acute kidney injury (AKI) and the combined effect of chronic kidney disease (CKD) and AKI in COVID-19 patients. Methods We collected data on patient demographics, comorbidities, chronic medications, vital signs, baseline laboratory test results and in-hospital treatment in patients with COVID-19 consecutively admitted to our Institution. Chronic kidney disease was defined as eGFR < 60 mL/min per 1.73 m 2 or proteinuria at urinalysis within 180 days prior to hospital admission. AKI was defined according to KDIGO criteria. The primary and secondary outcomes were the development of AKI and death. Results Of 777 patients eligible for the study, acute kidney injury developed in 176 (22.6%). Of these, 79 (45%) showed an acute worsening of a preexisting CKD, and 21 (12%) required kidney replacement therapy. Independent associates of AKI were chronic kidney disease, C-reactive protein (CRP) and ventilation support . Among patients with acute kidney injury, 111 died (63%) and its occurrence increased the risk of death by 60% (HR 1.60 [95% IC 1.21–2.49] p = 0.002) independently of potential confounding factors including hypertension, preexisting kidney damage, and comorbidities. Patients with AKI showed a significantly higher rate of deaths attributed to bleeding compared to CKD and the whole population (7.5 vs 1.5 vs 3.5%, respectively). Conclusion Awareness of kidney function, both preexisting CKD and development of acute kidney injury, may help to identify those patients at increased risk of death.

Individuals with Angelman syndrome (AS) present with severe intellectual disability alongside a social phenotype characterised by social communication difficulties and an increased drive for social engagement. As the social phenotype in this condition is poorly understood, we examined patterns of social attention and social modulation of attention in AS. Twenty-four individuals with AS and twenty-one young children with similar mental age were shown videos featuring unfamiliar actors who performed simple actions across two conditions: a playful condition, in which the actor showed positive facial emotions, and a neutral condition, in which the actor showed a neutral facial expression. During the passive observation of the videos, participants’ proportion of time spent watching the two areas of interest (faces and actions) was examined using eye-tracking technology. We found that the playful condition elicited increased proportion of fixations duration to the actor’s face compared to the neutral condition similarly across groups. Additionally, the proportion of fixations duration to the action area was similar across groups in the two conditions. However, children with AS looked towards the actor’s face for a shorter duration compared to the comparison group across conditions. This pattern of similarities and differences provides novel insight on the complex social phenotype of children with AS.

Individuals with Angelman syndrome (AS) are characterized by severe cognitive impairments alongside an enhanced drive for social engagement. As knowledge on imitation skills in this population is limited, we conducted the first controlled study of imitation in AS. We examined how 23 individuals with AS and 21 typically developing young children with similar mental age imitated novel actions in response to socially or non-socially engaging models, and in response to video-recorded versus live demonstrations of novel actions. Individuals with AS imitated as frequently and as accurately as typical young children in response to live demonstrations; but they imitated less frequently and less accurately in response to video-recorded demonstrations. Further, imitation was modulated by whether the demonstrator was socially engaging or emotionally neutral in the AS group, while this modulation was not present in the comparison group. Individuals with higher mental age imitated more frequently and more accurately across groups. Imitation performance in AS appears to be more modulated by the social context compared to typical infants and young children with similar mental age, possibly reflecting an enhanced drive for social engagement. A socially engaging instructional style might facilitate imitative learning in this population.

Background The overuse of antimicrobials favors the dissemination of antimicrobial resistance, as well as invasive fungal diseases and Clostridium difficile infections (CDI). In this study, we assessed the impact of a mixed educational and semi-restrictive antimicrobial stewardship (AMS) project in a large teaching hospital in Italy. Methods The AMS project was conducted from May 2014 to April 2016. It consisted of two initiatives in two consecutive periods: (1) educational activities; (2) semi-restrictive control of antimicrobial prescribing through a computerized software. The primary endpoint was consumption of antibacterials and antifungals. Secondary endpoints were incidence of CDI, methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI), carbapenem-resistant Klebsiella pneumoniae (CRKP) BSI, and Candida BSI. Results During the study period, a statistically significant reduction in consumption was observed for antibacterials (−1.45 defined daily doses (DDD)/1000 patient-days monthly, 95% confidence intervals [CI] −2.38 to −0.52, p 0.004), mainly driven by reductions in the use of fluoroquinolones, third/fourth generation cephalosporins, and carbapenems. No decrease in consumption of antifungals was observed (−0.04 DDD/1000 patient-days monthly, 95% CI −0.34 to +0.25, p 0.750). A statistically significant trend towards reduction was observed for incidence of CRKP BSI (incidence rate ratio 0.96, 95% CI 0.92–0.99, p 0.013). No statistically significant variations in trends were observed for CDI, MRSA BSI, and Candida BSI. Conclusions The mixed AMS project was effective in reducing the use of major antibacterials and the incidence of CRKP BSI. Further research is needed to assess the extent of long-term benefits of semi-restrictive approaches.

BackgroundThe goal of this study was to investigate the prevalence and factors associated with persistent viral shedding (PVS) in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.MethodsThis was a prospective observational study including all consecutive adults hospitalized with SARS-CoV-2 infection. When the first nasopharyngeal swab was positive for SARS-CoV-2 RNA (day 0), additional samples were obtained on days + 3, + 5, + 7 and then once every 7 days until virus detection was negative. PVS was defined as the duration of shedding of at least 21 days after diagnosis. The primary endpoint of this study was the prevalence of PVS.ResultsData were obtained regarding 121 consecutive hospitalized patients with SARS-CoV-2 infection (median age 66 years, male sex 65.3%). Overall, the prevalence of PVS was 38% (46/121 patients). According to univariate analysis, factors associated with PVS were immunosuppression (6.7% vs 21.7%, p = 0.02), increased interleukin-6 (IL-6) levels (≥ 35 ng/ml) at the time of diagnosis (43.4% vs 67.3%, p = 0.02), time from onset of symptoms to diagnosis (median days 7.0 vs 3.5, p = 0.001), intensive care unit admission (22.7% vs 43.5%, p = 0.02), and need for invasive mechanical ventilation (20.0% vs 41.3%, p = 0.01). The multivariate analysis indicated that immunosuppression, increased IL-6 levels at the time of diagnosis, time from onset of symptoms to diagnosis, and need for mechanical ventilation were independent factors associated with PVS.ConclusionsPVS was detected in up to 38% of hospitalized patients with SARS-CoV-2 infection and was strongly associated with immunosuppression, increased IL-6 levels, and the need for mechanical ventilation.

A technical error led to incorrect rendering of the author group in this article. The correct authorship is as follows: Daniele Roberto Giacobbe 1 , Valerio Del Bono 1 , Malgorzata Mikulska 1 , Giulia Gustinetti 1 , Anna Marchese 2 , Federica Mina 3 , Alessio Signori 4 , Andrea Orsi 5 , Fulvio Rudello 6 , Cristiano Alicino 5 , Beatrice Bonalumi 3 , Alessandra Morando 7 , Giancarlo Icardi 5 , Sabrina Beltramini 3 , Claudio Viscoli 1 ; On behalf of the San Martino Antimicrobial Stewardship Group