Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity

Individuals with the Neurofibromatosis-1 (NF1) inherited cancer syndrome exhibit neuronal dysfunction that predominantly affects the central nervous system (CNS). In this report, we demonstrate a unique vulnerability of CNS neurons, but not peripheral nervous system (PNS) neurons, to reduced Nf1 gene expression. Unlike dorsal root ganglion neurons, Nf1 heterozygous (Nf1+/−) hippocampal and retinal ganglion cell (RGC) neurons have decreased growth cone areas and neurite lengths, and increased apoptosis compared to their wild-type counterparts. These abnormal Nf1+/− CNS neuronal phenotypes do not reflect Ras pathway hyperactivation, but rather result from impaired neurofibromin-mediated cAMP generation. In this regard, elevating cAMP levels with forskolin or rolipram treatment, but not MEK or PI3-K inhibition, reverses these abnormalities to wild-type levels in vitro. In addition, Nf1+/− CNS, but not PNS, neurons exhibit increased apoptosis in response to excitotoxic or oxidative stress in vitro. Since children with NF1-associated optic gliomas often develop visual loss and Nf1 genetically-engineered mice with optic glioma exhibit RGC neuronal apoptosis in vivo, we further demonstrate that RGC apoptosis resulting from optic glioma in Nf1 genetically-engineered mice is attenuated by rolipram treatment in vivo. Similar to optic glioma-induced RGC apoptosis, the increased RGC neuronal death in Nf1+/− mice following optic nerve crush injury is also attenuated by rolipram treatment in vivo. Together, these findings establish a distinctive role for neurofibromin in CNS neurons with respect to vulnerability to injury, define a CNS-specific neurofibromin intracellular signaling pathway responsible for neuronal survival, and lay the foundation for future neuroprotective glioma treatment approaches

Impact of COVID-19 on emergency department use among home care recipients

BACKGROUND: The impact of COVID-19 pandemic on Emergency Department (ED) was remarkable throughout Europe. We focused upon ED utilization among integrated home care (IHC) recipients comparing ED between pandemic period with pre-pandemic (February -December 2020 and 2019, respectively) in Piedmont, Italy. METHODS: A retrospective observational study was conducted. All recipients of IHC during the two periods studied were enrolled and all ED visits that occurred among IHC recipients were accounted for. Several variables related to IHC admission, reason of ED visits and demographic characteristics were collected. The average of ED visits in pre-pandemic and pandemic periods were calculated. Analyses were stratified by all variables. RESULTS: Patients enrolled were 11968 in 2019 and 8938 in 2020. In 2019, 3573 patients had at least one ED visit and 1668 patients in 2020. Number of ED visits was 5503 in 2019 and 2197 in 2020. The average of ED visits in 2020 has reduced in comparison with 2019 (0.464 C.I. [0.44-0.489] and 0.24 C.I. [0.227-0.252], p < 0.001 in 2019 and 2020 respectively). This reduction is regardless of sex, age, duration of IHC, presence of a non-family caregiver or reason for ED visits, except for abdominal pain, cardiac rhythm alteration and gynaecological symptoms. The averages of ED visits were significantly lower for IHC recipients with neoplasm (0.549 C.I. [0.513-0.585] and 0.328 C.I. [0.298-0.358], p < 0.001, and with low level of emergency (1.77 C.I. [1.662-1.877] and 1.397 C.I. [1.348-1.447], p < 0.036), but an increase in mortality rate was not registered. CONCLUSIONS: Our results showed a reduction of ED visits among integrated home care recipients in pandemic period in comparison with pre-pandemic period. If the reduction can be the consequence of an unprepared health service that needs of necessary changes in its organization, these results suggest a great potential of the home care system to reduce the use of the hospital especially for low-risk conditions. KEY MESSAGES: • The COVID-19 pandemic overwhelmed health services of all European Countries. A reduced utilization of ED has been shown by literature, especially during the early phase of the COVID-19 pandemic. • We showed a reduction in IHC recipients and a great decrease in ED visits among IHC patients in 2020 versus 2019, mainly in oncological patients, while an increase in mortality rate was not reported

Severe and moderate seasonal influenza epidemics among Italian healthcare workers: A comparison of the excess of absenteeism

Background: This study aims to quantify the excess of sickness absenteeism among healthcare workers (HCWs), to estimate the impact of a severe versus moderate influenza season and to determine whether the vaccination rates are associated with reduced sickness absence. Methods: We investigated the excess absenteeism that occurred in a large Italian hospital, 5300 HCWs, during the severe influenza season of 2017/2018 and compared it with three moderate flu seasons (2010/2013). Data on influenza vaccinations and absenteeism were obtained from the hospital's databases. The data were split into two periods: the epidemic, from 42 to 17 weeks, and non-epidemic, defined as 18 to 41 weeks, which was used as the baseline. We stratified the absenteeism among HCWs in multiple variables. Results: Our study showed an increased absenteeism among HCWs during the epidemic period of severe season in comparison with non-epidemic periods, the absolute increase correlated with a relative increase of 70% (from 4.05 to 6.68 days/person). Vaccinated HCWs had less excess of absenteeism in comparison with non-vaccinated HCWs (1.74 vs 2.71 days/person). The comparison with the moderate seasons showed a stronger impact on HCW sick absenteeism in the severe season (+0.747days/person, P =.03), especially among nurses and HCWs in contact with patients (+1.53 P <.01; +1.19 P <.01). Conclusions: In conclusion, a severe influenza epidemic has greater impacts on the absenteeism among HCWs than a moderate one. Although at a low rate, a positive effect of vaccination on absenteeism is present, it may support healthcare facilities to recommend vaccinations for their workers

The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation.

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma. Similar to the GFAP-Cre transgenic strain previously employed to generate Nf1 optic gliomas, Olig2+ cells also give rise to astrocytes in the murine optic nerve in vivo. However, in contrast to the GFAP-Cre strain where somatic Nf1 inactivation in embryonic neural progenitor/stem cells (Nf1flox/mut; GFAP-Cre mice) results in optic gliomas by 3 months of age in vivo, mice with Nf1 gene inactivation in Olig2+ OPCs (Nf1flox/mut; Olig2-Cre mice) do not form optic gliomas until 6 months of age. These distinct patterns of glioma latency do not reflect differences in the timing or brain location of somatic Nf1 loss. Instead, they most likely reflect the cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at 3 months of age. Collectively, these data demonstrate that the cell of origin dictates the time to tumorigenesis in murine optic glioma

Emergency-department accesses in home care paediatric patients: Occurrence and risks of use in a six-year retrospective investigation in Northern Italy

Objective To assess the determinants of ED use in paediatric patients enrolled in an Integrated Paediatric Home Care (IPHC) program. Methods A retrospective study was conducted using administrative databases on a cohort of patients enrolled in an IPHC program between January 1st, 2012, and December 31st, 2017, in Northern Italy. ED visits that occurred during the IPHC program were considered. Data were collected considering sociodemographic, clinical and organizational variables. A multivariable stepwise logistic regression analysis was performed. The dependent variable to identify possible associations was ED visit. Results A total of 463 ED visits occurred in 465 children, with an incidence rate of 1. The risk of ED visits significantly increased among children involved in the IPHC program after hospital discharge (OR 1.94). Additionally, the risk of ED visits increased significantly as the duration of IPHC increased (OR 5.80 between 101 and 200 days, to OR 7.84 between 201 and 300 days, OR 12.54 between 301 and 400 days and OR 18.67 to more than 400 days). Conclusion The overall results represent a practical perspective to contribute improving both the service quality of IPHC and reducing low acuity and improper ED use

Predictors and trajectories of ED visits among patients receiving palliative home care services: Findings from a time series analysis (2013-2017)

Background: Current policies recommend integrating home care and palliative care to enable patients to remain at home and avoid unnecessary hospital admission and emergency department (ED) visits. The Italian health care system had implemented integrated palliative home care (IHPC) services to guarantee a comprehensive, coordinated approach across different actors and to reduce potentially avoidable ED visits. This study aimed to analyze the trajectories of ED visit rates among patients receiving IHPC in the Italian healthcare system, as well as the association between socio-demographic, health supply, and clinical factors. Methods: A pooled, cross-sectional, time series analysis was performed in a large Italian region in the period 2013-2017. Data were taken from two databases of the official Italian National Information System: Home Care Services and ED use. A clinical record is opened at the time a patient is enrolled in IHPC and closed after the last service is provided. Every such clinical record was considered as an IHPC event, and only ED visits that occurred during IHPC events were considered. Results: The 20,611 patients enrolled in IHPC during the study period contributed 23,085 IHPC events; ≥1 ED visit occurred during 6046 of these events. Neoplasms accounted for 89% of IHPC events and for 91% of ED visits. Although there were different variations in ED visit rates during the study period, a slight decline was observed for all diseases, and this decline accelerated over time (b = - 0.18, p = 0.796, 95% confidence interval [CI] = - 1.59;1.22, b-squared = - 1.25, p < 0.001, 95% CI = -1.63;-0.86). There were no significant predictors among the socio-demographic factors (sex, age, presence of a non-family caregiver, cohabitant family members, distance from ED), health supply factors (proponent of IHPC) and clinical factors (prevalent disorder at IHPC entry, clinical symptoms). Conclusion: Our results show that use of ED continues after enrollment in IHPC, but the trend of this use declines over time. As no significant predictive factors were identified, no specific interventions can be recommended on which the avoidable ED visits depend

Burden of COVID-19: Disability-Adjusted Life Years (DALYs) across 16 European countries

OBJECTIVE: The aim of this study is to measure and compare the burden of disease of COVID-19 pandemic in 16 EU/EEA countries through the estimation of Disability-Adjusted Life Years (DALYs) over a long period of time