SARS-CoV-2 infection and replication in human gastric organoids

COVID-19 typically manifests as a respiratory illness, but several clinical reports have described gastrointestinal symptoms. This is particularly true in children in whom gastrointestinal symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. These observations raise the question of whether the virus can replicate within the stomach. Here we generate gastric organoids from fetal, pediatric, and adult biopsies as in vitro models of SARS-CoV-2 infection. To facilitate infection, we induce reverse polarity in the gastric organoids. We find that the pediatric and late fetal gastric organoids are susceptible to infection with SARS-CoV-2, while viral replication is significantly lower in undifferentiated organoids of early fetal and adult origin. We demonstrate that adult gastric organoids are more susceptible to infection following differentiation. We perform transcriptomic analysis to reveal a moderate innate antiviral response and a lack of differentially expressed genes belonging to the interferon family. Collectively, we show that the virus can efficiently infect the gastric epithelium, suggesting that the stomach might have an active role in fecal-oral SARS-CoV-2 transmission.Several clinical reports have described gastrointestinal symptoms for COVID-19, though whether the virus can replicate within the stomach remains unclear. Here the authors generate gastric organoids from human biopsies and show that the virus can efficiently infect gastric epithelium, suggesting that the stomach might have an active role in fecal-oral transmission

Therapeutic homology-independent targeted integration in retina and liver

Challenges to the widespread application of gene therapy with adeno-associated viral (AAV) vectors include dominant conditions due to gain-of-function mutations which require allele-specific knockout, as well as long-term transgene expression from proliferating tissues, which is hampered by AAV DNA episomal status. To overcome these challenges, we used CRISPR/Cas9-mediated homology-independent targeted integration (HITI) in retina and liver as paradigmatic target tissues. We show that AAV-HITI targets photoreceptors of both mouse and pig retina, and this results in significant improvements to retinal morphology and function in mice with autosomal dominant retinitis pigmentosa. In addition, we show that neonatal systemic AAV-HITI delivery achieves stable liver transgene expression and phenotypic improvement in a mouse model of a severe lysosomal storage disease. We also show that HITI applications predominantly result in on-target editing. These results lay the groundwork for the application of AAV-HITI for the treatment of diseases affecting various organs

Engineering Reconnaissance Following the October 2016 Central Italy Earthquakes - Version 2

Between August and November 2016, three major earthquake events occurred in Central Italy. The first event, with M6.1, took place on 24 August 2016, the second (M5.9) on 26 October, and the third (M6.5) on 30 October 2016. Each event was followed by numerous aftershocks. As shown in Figure 1.1, this earthquake sequence occurred in a gap between two earlier damaging events, the 1997 M6.1 Umbria-Marche earthquake to the north-west and the 2009 M6.1 L’Aquila earthquake to the south-east. This gap had been previously recognized as a zone of elevated risk (GdL INGV sul terremoto di Amatrice, 2016). These events occurred along the spine of the Apennine Mountain range on normal faults and had rake angles ranging from -80 to -100 deg, which corresponds to normal faulting. Each of these events produced substantial damage to local towns and villages. The 24 August event caused massive damages to the following villages: Arquata del Tronto, Accumoli, Amatrice, and Pescara del Tronto. In total, there were 299 fatalities (www.ilgiornale.it), generally from collapses of unreinforced masonry dwellings. The October events caused significant new damage in the villages of Visso, Ussita, and Norcia, although they did not produce fatalities, since the area had largely been evacuated. The NSF-funded Geotechnical Extreme Events Reconnaissance (GEER) association, with co-funding from the B. John Garrick Institute for the Risk Sciences at UCLA and the NSF I/UCRC Center for Unmanned Aircraft Systems (C-UAS) at BYU, mobilized a US-based team to the area in two main phases: (1) following the 24 August event, from early September to early October 2016, and (2) following the October events, between the end of November and the beginning of December 2016. The US team worked in close collaboration with Italian researchers organized under the auspices of the Italian Geotechnical Society, the Italian Center for Seismic Microzonation and its Applications, the Consortium ReLUIS, Centre of Competence of Department of Civil Protection and the DIsaster RECovery Team of Politecnico di Torino. The objective of the Italy-US GEER team was to collect and document perishable data that is essential to advance knowledge of earthquake effects, which ultimately leads to improved procedures for characterization and mitigation of seismic risk. The Italy-US GEER team was multi-disciplinary, with expertise in geology, seismology, geomatics, geotechnical engineering, and structural engineering. The composition of the team was largely the same for the two mobilizations, particularly on the Italian side. Our approach was to combine traditional reconnaissance activities of on-ground recording and mapping of field conditions, with advanced imaging and damage detection routines enabled by state-of-the-art geomatics technology. GEER coordinated its reconnaissance activities with those of the Earthquake Engineering Research Institute (EERI), although the EERI mobilization to the October events was delayed and remains pending as of this writing (April 2017). For the August event reconnaissance, EERI focused on emergency response and recovery, in combination with documenting the effectiveness of public policies related to seismic retrofit. As such, GEER had responsibility for documenting structural damage patterns in addition to geotechnical effects. This report is focused on the reconnaissance activities performed following the October 2016 events. More information about the GEER reconnaissance activities and main findings following the 24 August 2016 event, can be found in GEER (2016). The objective of this document is to provide a summary of our findings, with an emphasis of documentation of data. In general, we do not seek to interpret data, but rather to present it as thoroughly as practical. Moreover, we minimize the presentation of background information already given in GEER (2016), so that the focus is on the effects of the October events. As such, this report and GEER (2016) are inseparable companion documents. Similar to reconnaissance activities following the 24 August 2016 event, the GEER team investigated earthquake effects on slopes, villages, and major infrastructure. Figure 1.2 shows the most strongly affected region and locations described subsequently pertaining to: 1. Surface fault rupture; 2. Recorded ground motions; 3. Landslides and rockfalls; 4. Mud volcanoes; 5. Investigated bridge structures; 6. Villages and hamlets for which mapping of building performance was performed

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Withdrawal of mechanical ventilation in amyotrophic lateral sclerosis patients: a multicenter Italian survey

Background: Law 219/2017 was approved in Italy in December 2017, after a years-long debate on the autonomy of healthcare choices. This Law, for the first time in Italian legislation, guarantees the patient's right to request for withdrawal of life-sustaining treatments, including mechanical ventilation (MV). Objective: To investigate the current status of MV withdrawal in amyotrophic lateral sclerosis (ALS) patients in Italy and to assess the impact of Law 219/2017 on this practice. Methods: We conducted a Web-based survey, addressed to Italian neurologists with expertise in ALS care, and members of the Motor Neuron Disease Study Group of the Italian Society of Neurology. Results: Out of 40 ALS Italian centers, 34 (85.0%) responded to the survey. Law 219/2017 was followed by an increasing trend in MV withdrawals, and a significant increase of neurologists involved in this procedure (p 0.004). However, variations across Italian ALS centers were observed, regarding the inconsistent involvement of community health services and palliative care (PC) services, and the intervention and composition of the multidisciplinary team. Conclusions: Law 219/2017 has had a positive impact on the practice of MV withdrawal in ALS patients in Italy. The recent growing public attention on end-of-life care choices, along with the cultural and social changes in Italy, requires further regulatory frameworks that strengthen tools for self-determination, increased investment of resources in community and PC health services, and practical recommendations and guidelines for health workers involved

First detection of X-ray polarization from the accreting neutron star 4U 1820-303

This paper reports the first detection of polarization in the X-rays for atoll-source 4U 1820-303, obtained with the Imaging X-ray Polarimetry Explorer (IXPE) at 99.999% confidence level (CL). Simultaneous polarimetric measurements were also performed in the radio with the Australia Telescope Compact Array (ATCA). The IXPE observations of 4U 1820-303 were coordinated with Swift-XRT, NICER, and NuSTAR aiming to obtain an accurate X-ray spectral model covering a broad energy interval. The source shows a significant polarization above 4 keV, with a polarization degree of 2.0(0.5)% and a polarization angle of -55(7) deg in the 4-7 keV energy range, and a polarization degree of 10(2)% and a polarization angle of -67(7) deg in the 7-8 keV energy bin. This polarization also shows a clear energy trend with polarization degree increasing with energy and a hint for a position-angle change of about 90 deg at 96% CL around 4 keV. The spectro-polarimetric fit indicates that the accretion disk is polarized orthogonally to the hard spectral component, which is presumably produced in the boundary/spreading layer. We do not detect linear polarization from the radio counterpart, with a 99.97% upper limit of 50% at 7.25 GHz

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria