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Background: Heart failure (HF)-related mortality has been exacerbated by the COVID-19 pandemic; however, it is unclear how healthcare reassessment has contributed to the excess mortality versus SARS-CoV-2 infection itself. We aimed to assess how the pandemic affected the therapeutic management and prognosis of HF patients. Methods: We retrospectively reviewed the healthcare utilization databases of the Lombardy region (Italy) to identify all newly-diagnosed HF patients from January 2018 to December 2021. Outcomes were the utilization of HF therapies (Sacubitril/Valsartan; cardiac resynchronization therapy [CRT] and/or implantable cardioverter-defibrillator [ICD]; mechanical circulatory support [MCS]; heart transplantation [HTX]) and mortality. Cox regression models were fitted to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for outcomes associated with the pandemic. Results: 36,130 and 17,263 patients were identified in the pre-pandemic and pandemic eras, respectively. The pandemic reduced Sacubitril/Valsartan utilization (HR = 0.77, 95% CI: 0.65-0.91) and CRT/ICD implantation (HR = 0.85, 95% CI: 0.78-0.92), but not MCS (HR = 1.11, 95% CI: 0.86-1.43) and HTX (HR = 0.88, 95% CI: 0.70-1.09). An increased mortality risk was observed during the pandemic (HR = 1.19, 95% CI: 1.15-1.23), which was attributable to SARS-CoV-2 infection (HR for non-COVID-19-related mortality = 1.01, 95% CI: 0.97-1.04). Conclusions: The COVID-19 pandemic was associated with a reduction in medical and interventional therapies for HF and an increase in mortality for HF patients.

Context: Patients with diabetes are at increased risk of dying from liver-related events, but little is known on whether this increased risk changed in recent years. Objective: The aim of the present study is to describe time trends in cause-specific liver-related mortality in people with and without diabetes from the general Italian population. Methods: Data were retrieved from the healthcare utilization databases of Lombardy, a region of Italy that accounts for about 16% (almost ten million) of its population. Annual cause-specific mortality rates and proportionate mortality were computed among individuals with and without diabetes from 2010 to 2019. Liver-related deaths were categorized as viral, alcohol related and non-viral non-alcohol related (NVNA). Results: Liver diseases were responsible for 2% and 1% of deaths in people with and without diabetes (2019). Among patients with diabetes, the crude mortality rate for liver diseases decreased from 1.13 to 0.64 deaths per 1,000 person-years from 2010 to 2019. The largest proportion of liver-related deaths was attributable to NVNA diseases and it increased from 63% in 2010 to 68% in 2019, with a corresponding relative reduction of viral causes (from 27% to 23%). The Standardized Mortality Ratio for patients with diabetes was 3.35 (95% CI 2.96-3.76) for NVNA, 1.66 (95% CI 1.33-2.01) for viral hepatitis and 1.61 (95% CI 1.13-2.17) for alcoholic liver disease and it remained relatively stable over time. Excess mortality risk in patients with diabetes for liver-related mortality was higher than for cardiovascular mortality and cancer. Conclusion: While liver-related mortality rates decreased significantly among patients with diabetes, NVNA causes comprised the majority of cases. Excess mortality for liver-related causes in patients with diabetes compared with controls remained constant in the studied period.

Objective:To compare adherence to antihypertensive treatment between patients prescribed a three-drug single-pill combination (SPC) of perindopril/amlodipine/indapamide (P/A/I) vs. the combination of an angiotensin-converting enzyme inhibitor (ACEI), a calcium-channel blocker (CCB), and a diuretic (D) as a two-drug SPC plus a third drug given separately.Methods:Using the healthcare utilization database of the Lombardy Region (Italy), the 28 210 patients, aged at least 40 years, who were prescribed P/A/I SPC during 2015-2018 were identified and the date of the first prescription was defined as the index date. For each patient prescribed the SPC, a comparator who started ACEI/CCB/D treatment as a two-pill combination was considered. Adherence to the triple combination was assessed over the year after the index date as the proportion of the follow-up days covered by prescription (PDC). Patients who had a PDC >75% were defined as highly adherent to drug therapy. Log-binomial regression models were fitted to estimate the risk ratio of treatment adherence in relation to the drug treatment strategy.Results:About 59 and 25% of SPC and two-pill combination users showed high adherence, respectively. Compared with patients under a three-drug two-pill combination, those who were treated with the three-drug SPC had a higher propensity to be highly adherent to the triple combination (2.38, 95% confidence interval: 2.32-2.44). This was the case regardless of the sex, age, comorbidities, and number of co-treatments.Conclusions:In a real-life setting, patients under three-drug SPC exhibited more frequently a high adherence to antihypertensive treatment than those prescribed a three-drug two-pill combination.

Purpose. Randomised controlled trials have shown that renal denervation lowers office and ambulatory blood pressure. The aim of the present study was to evaluate whether patients undergoing renal denervation procedure in a real-life setting have a reduction in antihypertensive drug prescription over the subsequent years. Material and methods. Using the healthcare utilisation database of the Lombardy Region (Italy), the 136 patients who, during the period 2011–2016, were prescribed four or more antihypertensive drugs and underwent renal denervation were included in the study cohort. The number and type of antihypertensive drugs were assessed over the year before and during the three-year period after renal denervation. Results. The median age of the patients was 67 years and 68% of them were men. Based on a multisource comorbidity score, about 40% of patients showed a poor or very poor clinical status. Before renal denervation, the majority of the patients were prescribed four or five antihypertensive drugs. The number of drugs decreased after the denervation and reached 55% after three years. Over the same period, patients prescribed six drugs decreased from 18% to 2%. All antihypertensive drugs were less prescribed throughout the post denervation period. Compared to the year before the denervation, after three years prescription of diuretics was reduced by 15%, calcium channel blockers by 21%, ACE-inhibitors by 32%, angiotensin receptor blockers by 22%, beta-blockers by 20%, and alfa-blockers by 30%. Use of antihypertensive drugs exhibited a reduction also in an age, sex, and clinically matched control group with no renal denervation to an extent, however, much lower than in denervated patients (p-value = 0.013). Conclusion. In the real-life setting, patients who underwent renal denervation had a clearcut reduction in antihypertensive drug prescription over the following years.Plain Language Summary Patients exhibited a reduction in the prescription of antihyperten

Context: It is still debated whether prolonged use of proton pump inhibitors (PPIs) might affect metabolic health. Objective: To investigate the relationship between prolonged use of PPIs and the risk of developing diabetes. Methods: We performed a case-control study nested into a cohort of 777 420 patients newly treated with PPIs between 2010 and 2015 in Lombardy, Italy. A total of 50 535 people diagnosed with diabetes until 2020 were matched with an equal number of controls that were randomly selected from the cohort members according to age, sex, and clinical status. Exposure to treatment with PPIs was assessed in case-control pairs based on time of therapy. A conditional logistic regression model was fitted to estimate the odds ratios and 95% CIs for the exposure-outcome association, after adjusting for several covariates. Sensitivity analyses were performed to evaluate the robustness of our findings. Results: Compared with patients who used PPIs for[removed]2 years, respectively. The results were consistent when analyses were stratified according to age, sex, and clinical profile, with higher odds ratios being found in younger patients and those with worse clinical complexity. Sensitivity analyses revealed that the association was consistent and robust. Conclusions: Regular and prolonged use of PPIs is associated with a higher risk of diabetes. Physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use.

For effective lakes’ management, high-frequent water quality data on a synoptic scale are essential. The aim of this study is to test the suitability of the latest generation of satellite sensors to provide information on lake water quality parameters for the five largest Italian subalpine lakes. In situ data of phytoplankton composition, chlorophyll-a (chl-a) concentration and water reflectance were used in synergy with satellite observations to map some algal blooms in 2016. Chl-a concentration maps were derived from satellite data by applying a bio-optical model to satellite data, previously corrected for atmospheric effects. Results were compared with in situ data, showing good agreement. The shape and magnitude of water reflectance from different satellite data were consistent. Output chl-a concentration maps, show the distribution within each lake during blooming events, suggesting a synoptic view is required for these events monitoring. Maps show the dynamic of bloom events with concentration increasing from 2 up to 7 mg m−3 and dropping again to initial value in less than 20 days. Latest generation sensors were shown to be valuable tools for lakes monitoring, thanks to frequent, free of charge data availability over long time periods

Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eBi-Mecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.

Dravet syndrome (DS) is a severe epileptic encephalopathy caused mainly by heterozygous loss-of-function mutations of the SCN1A gene, indicating haploinsufficiency as the pathogenic mechanism. Here we tested whether catalytically dead Cas9 (dCas9)-mediated Scn1a gene activation can rescue Scn1a haploinsufficiency in a mouse DS model and restore physiological levels of its gene product, the Nav1.1 voltage gated sodium channel. We screened single guide RNAs (sgRNAs) for their ability to stimulate Scn1a transcription in association with the dCas9 activation system. We identified a specific sgRNA that increases Scn1a gene expression levels in cell lines and primary neurons with high specificity. Nav1.1 protein levels were augmented, as was the ability of wild-type immature GABAergic interneurons to fire action potentials. A similar enhancement of Scn1a transcription was achieved in mature DS interneurons, rescuing their ability to fire. To test the therapeutic potential of this approach, we delivered the Scn1a-dCas9 activation system to DS pups using adenoassociated viruses. Parvalbumin interneurons recovered their firing ability, and febrile seizures were significantly attenuated. Our results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach to DS and other disorders resulting from altered gene dosage.

The aim of the study is to test the suitability of Sentinel-2 MSI for mapping phytoplankton in turbid extremely productive inland waters with recurrent cyanobacterial bloom that represent a major concern. These blooms can have an influence on health care costs, on the costs associated with the treatment of water intended for human consumption and on the tourism business. The study sites investigated in this work include the three lakes of Mantua (Italy), a system of fluvial lakes characterised by a patchy distribution of phytoplankton. These shallow, nutrient-enriched and turbid waters host different primary producers and undergo pronounced discharge variations. The other site is the Curonian lagoon (Lithuania and Russian Federation) and with a surface of 1584 km2 is largest lagoon of Europe. It is also very shallow with waters readily mixed by wind action, although weak stratification can occur temporarily during the summer. The system is also highly eutrophic due to external nutrient loads from the tributary Nemunas River. The presence of cyanobacterial toxic metabolites, is a major concern for water quality and human health in the region. The study areas are part of two research projects (FP-7 INFORM (copernicus-inform.eu) and BLASCO (projectblasco.it)) which have been supporting field activities in the last three years gathering fundamental data for evaluating Sentinel-2 data. Five days match-ups with satellite acquisitions resulted available for evaluating satellite products in terms of concentrations of chlorophyll-a (chl-a), as proxy of phytoplankton. Field measurements include aquatic optical properties and limnological data that allowed the development of semi-empirical adaptive algorithms and of spectral inversion techniques of bio-optical modelling to retrieve chl-a. Depending on water leaving reflectance the approaches were integrated because bio-optical modelling inversion performed better for lower chl-a concentrations (<10 mgm-3), while adaptive semi

A first synoptic and trans-domain overviewof plankton dynamics was conducted across the aquatic sites belonging to the Italian Long-Term Ecological Research Network (LTER-Italy). Based on published studies, checked and complemented with unpublished information, we investigated phytoplankton and zooplankton annual dynamics and long-term changes across domains: from the large subalpine lakes to mountain lakes and artificial lakes, from lagoons to marine coastal ecosystems. This study permitted identifying common and unique environmental drivers and ecological functional processes controlling seasonal and long-termtemporal course. The most relevant patterns of plankton seasonal succession were revealed, showing that the driving factors were nutrient availability, stratification regime, and freshwater inflow. Phytoplankton and mesozooplankton displayed a wide interannual variability at most sites. Unidirectional or linear long-term trends were rarely detected but all sites were impacted across the years by at least one, but in many case several major stressor(s): nutrient inputs, meteo-climatic variability at the local and regional scale, and direct human activities at specific sites. Different climatic and anthropic forcings frequently co-occurred, whereby the responses of plankton communities were the result of this environmental complexity. Overall, the LTER investigations are providing an unparalleled framework of knowledge to evaluate changes in the aquatic pelagic systems and management options

Phytoplankton (PCC) and prokaryoplankton community compositions were studied in five perialpine lakes (Garda, Maggiore, Como, Iseo, and Lugano) of different trophic conditions and mixing regimes, using inverted microscopy and CARD-FISH technique. The aim of this research was to assess, for the first time in these lakes, the relationships among PCC, bacteria, and archaea, and the effects of environmental drivers. We observed a clear difference of PCC compositions in spring and summer. All the lakes showed Bacillariophyta dominating in spring, whereas in summer, there were remarkable differences of PCC. Prokaryoplankton composition showed more pronounced differences in the vertical profile than those between spring and summer. The oligomictic lakes showed a uniform vertical gradient of prokaryotes in spring, while in the meromictic lakes, their abundances were incremented with depth. In summer, the prokaryotic community changed, and niche differentiation occurred in almost all lakes. In conclusion, our study showed a general pattern, common to all the lakes, of a first appearance of the large-sized “opportunistic” bacteria in spring, followed by ultramicrobacteria, less vulnerable to predation in summer. Significant correlations between a few PCC and bacterial groups were found, thus elucidating that functional interactions can be the key to understand plankton successions