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Background Noninvasive respiratory support (NIRS) has been diffusely employed outside the intensive care unit (ICU) to face the high request of ventilatory support due to the massive influx of patients with acute respiratory failure (ARF) caused by coronavirus-19 disease (COVID-19). We sought to summarize the evidence on clinically relevant outcomes in COVID-19 patients supported by NIV outside the ICU. Methods We searched PUBMED®, EMBASE®, and the Cochrane Controlled Clinical trials register, along with medRxiv and bioRxiv repositories for pre-prints, for observational studies and randomized controlled trials, from inception to the end of February 2021. Two authors independently selected the investigations according to the following criteria: (1) observational study or randomized clinical trials enrolling ≥ 50 hospitalized patients undergoing NIRS outside the ICU, (2) laboratory-confirmed COVID-19, and (3) at least the intra-hospital mortality reported. Preferred Reporting Items for Systematic reviews and Meta-analysis guidelines were followed. Data extraction was independently performed by two authors to assess: investigation features, demographics and clinical characteristics, treatments employed, NIRS regulations, and clinical outcomes. Methodological index for nonrandomized studies tool was applied to determine the quality of the enrolled studies. The primary outcome was to assess the overall intra-hospital mortality of patients under NIRS outside the ICU. The secondary outcomes included the proportions intra-hospital mortalities of patients who underwent invasive mechanical ventilation following NIRS failure and of those with ‘do-not-intubate’ (DNI) orders. Results Seventeen investigations (14 peer-reviewed and 3 pre-prints) were included with a low risk of bias and a high heterogeneity, for a total of 3377 patients. The overall intra-hospital mortality of patients receiving NIRS outside the ICU was 36% [30–41%]. 26% [21–30%] of the patients failed NIRS and required intubation, with an intra-hospital mortality rising to 45% [36–54%]. 23% [15–32%] of the patients received DNI orders with an intra-hospital mortality of 72% [65–78%]. Oxygenation on admission was the main source of between-study heterogeneity. Conclusions During COVID-19 outbreak, delivering NIRS outside the ICU revealed as a feasible strategy to cope with the massive demand of ventilatory assistance. Registration PROSPERO, https://www.crd.york.ac.uk/prospero/ , CRD42020224788, December 11, 2020.

Background and Objectives: Hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic condition characterized by recurrent, potentially life-threatening episodes of angioedema. Long-term prophylaxis (LTP) is essential for decreasing the frequency and severity of attacks. This study aims to compare the safety profiles of two first-line LTP therapies, both of which inhibit kallikrein: berotralstat (oral) and lanadelumab (subcutaneous), using data from the WHO’s VigiBase pharmacovigilance database. Materials and Methods: The study employed a retrospective quantitative design, utilizing the World Health Organization’s pharmacovigilance database, VigiAccess, which contains individual case safety reports of adverse drug reactions (ADRs) to identify cases of ADRs associated with HAE-C1-INH long-term prophylaxis. Results: A total of 644 reports for berotralstat and 3432 reports for lanadelumab were analyzed. Berotralstat was mainly associated with gastrointestinal adverse events (47.9%), while lanadelumab was linked to injection site reactions (45.9%), infections (23.3%), musculoskeletal and connective tissue disorders (10%), immune system disorders (5.3%), vascular disorders (4.7%), and metabolic issues (3.9%). Female patients were more frequently affected in both groups. Statistically significant differences were observed, reflecting the differences in administration methods and pharmacological profiles between the two drugs. Limitations include the self-reported nature of the data and the absence of detailed clinical information. Conclusions: The results confirmed the literature’s data on the gastrointestinal adverse effects of berotralstat, as well as site reactions and infections associated with lanadelumab. Notably, musculoskeletal and connective tissue disorders, immune system disorders, vascular disorders, and metabolic issues occurred more frequently in patients using lanadelumab.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare necrotizing vasculitis characterized by eosinophilic inflammation that was traditionally treated with corticosteroids associated with other immunosuppressants. Over the last years different biological therapies targeting IL-5/IL-5 receptor have become available and have been employed to tackle this challenging condition. Aim of the present study is to synthesis the evidence on the clinical presentation of this disease and on the efficacy of the newly available therapeutic strategies. In June 2024 PubMed, Embase and the Cochrane library were searched for studies reporting on EGPA patients being treated by means of different anti IL-5 or anti eosinophils biological therapies. Risk of bias was assessed through the ROBINS-I and RoB2 tools according to study design. Proportion meta-analysis was employed to synthetize data on EGPA clinical manifestations, while data on treatment outcomes was analyzed descriptively due to the high heterogeneity. The present systematic review included 25 studies on a total of 1131 patients. Asthma was present in 99.2% of the patients, Sinonasal involvement in 87.0% and ANCA positivity in 22.8%. The explored treatments consisted in Benralizumab 30 mg every 4 weeks, Mepolizumab 100 mg or 300 mg every 4 weeks and Reslizumab 3mg/Kg every 4 weeks. All the anti-IL-5/IL-5 receptor molecules proved efficacious in remission control and corticosteroid tapering. The available data strongly suggests integrating anti IL-5/IL-5 receptor therapies into EGPA treatment strategies, to enhance patients' outcomes and reduce the long term side effects of prolonged corticosteroid therapy.

Berotralstat, the first oral plasma kallikrein inhibitor approved for hereditary angioedema (HAE) prophylaxis, may be associated with gastrointestinal (GI) side effects, particularly during the first three months of therapy. Probiotics have been shown to reduce GI disturbances in several conditions. This pilot study described GI tolerability in patients receiving initiation-phase probiotic co-administration alongside berotralstat and explored whether this supportive strategy merits further controlled evaluation. We analyzed 25 adolescents and adults with HAE treated with berotralstat across six Italian centers (December 2023-November 2025). All patients received probiotics during the early treatment phase. Demographic and clinical data, side effects, and monthly HAE attack rates were collected. Severity of complaints was graded using the Common Terminology Criteria for Adverse Events (CTCAE). Participants were 60% females, and the mean age for the cohort was 45 years (range 12-82). The most common probiotics were , , and . GI complaints occurred in 5/25 patients (20%); only 3/25 (12%) experienced GI side effects while receiving probiotics. 2/25 GI complaints occurred after probiotic discontinuation. No serious side effects were reported. Mean monthly attack rate decreased from 2.6 to 0.8 attacks per month, ~3.3-fold reduction from baseline. Probiotic co-administration during early berotralstat therapy was accompanied by a low incidence of GI side effects, while clinical effectiveness was maintained. These preliminary findings support further controlled studies to validate probiotics as a supportive strategy for improving the tolerability of berotralstat.

Diabetes mellitus and heart failure are two diseases that are commonly found together, in particular in older patients. High blood glucose has a detrimental effect on the cardiovascular system, and worse glycemic control contributes to the onset and the recrudesce of heart failure. Therefore, any specific treatment aimed to reduce glycated hemoglobin may, in turn, have a beneficial effect on heart failure. Sodium-glucose cotransporter-2 inhibitors have been initially developed for the treatment of type 2 diabetes mellitus, and their significant action is to increase glycosuria, which in turn causes a reduction in glucose blood level and contributes to the reduction of cardiovascular risk. However, recent clinical trials have progressively demonstrated that the glycosuric effect of the sodium-glucose cotransporter-2 inhibitors also have a diuretic effect, which is a crucial target in the management of patients with heart failure. Additional studies also documented that sodium-glucose cotransporter-2 inhibitors improve the therapeutical management of heart failure, independently by the glycemic control and, therefore, by the presence of diabetes mellitus. In this review, we analyzed studies and trials demonstrating the efficacy of sodium-glucose cotransporter-2 inhibitors in treating chronic and acute heart failure.

Background: Diabetes mellitus (DM) is more common in people living with HIV (PLWH) than in HIV-negative patients. Here we aimed to describe the response of PLWH with DM to glucose-lowering therapies in a reference hospital of northern Italy. Setting: 200 PLWH and DM were identified from the database of our clinic. Methods: Good control of DM was defined as having fasting glucose <130 mg/dl or HbA1c < 53 mmol/mol. The distribution of glucose-lowering therapies in PLWH was compared with that of HIV-negative patients with DM. Results: Mean total fasting glucose and HbA1C were 143 ± 50 mg/dl (51% exceeding the 130 mg/dl cutoff) and 51 ± 16 mmol/mol (30% exceeding the 53 mmol/mol cutoff), respectively. PLWH were less treated with dipeptidyl peptidase-4 inhibitors (1.7% versus 9.6%, p < 0.01) and sulfonylureas (3.3% versus 13.2%, p < 0.01), being conversely more frequently treated with metformin (53.8% versus 37.7%, p < 0.01), glifozins plus metformin (7.1% versus 2.0%, p < 0.05) or insulin plus other glucose-lowering agents (5.5% versus 0.5%, p < 0.01). Conclusion: An underuse of dipeptidyl peptidase-4 inhibitors was found which was, however, counterbalanced by a higher use of combination of drugs (including glifozins). A rational assessment of drug-drug interactions would contribute to a better selection of the best glucose lowering agent for each antiretroviral therapy.

Cardiovascular pathologies represent the first cause of death in uremic patients and are among the leading causes of mortality in patients with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH). Before 2020, the most common treatment for long-term prophylaxis in HAE-C1INH patients in Italy was attenuated androgen, which may increase cardiovascular risk by multiple mechanisms. We present a case report of a 56-year-old patient with HAE-C1INH type I affected by IgA nephropathy with severe kidney impairment. The patient experienced a first kidney transplant and, after late rejection, underwent a second kidney transplant. Further comorbidities included obesity, hypertensive cardiomyopathy, HCV liver disease, and dyslipidemia. His prophylactic therapy to prevent angioedema attacks had consisted of attenuated androgens for about 40 years. Since 2020, new modern targeted therapy for LTP, particularly lanadelumab, has shown promising results. The majority of patients with attenuated androgens have been successfully switched to lanadelumab, including our patient. Since introducing lanadelumab (300 mg subcutaneously every two weeks; after a six-month attack-free period, the dosing interval of lanadelumab was extended to four weeks), the patient has not experienced any acute HAE attack and did not report any adverse events. Moreover, we observed decreased total cholesterol, C-LDL, and body mass index, reducing the Matsushita et al. score for ten years of cardiovascular risk from 13.2% to 9.3%. lanadelumab is effective and safe in preventing hereditary angioedema attacks, as well as in reducing cardiovascular risk in an immunosuppressed patient with significant comorbidities. The successful outcomes of this case highlight the potential of lanadelumab as a promising prophylactic therapy.

Background: Although more than four years have passed since the pandemic began, SARS-CoV-2 continues to be of concern. Therefore, research into the underlying mechanisms that contribute to the development of the disease, especially in more severe forms, remains a priority. Sustained activation of the complement (CS), contact (CAS), and fibrinolytic and kinin–kallikrein systems (KKS) has been shown to play a central role in the pathogenesis of the disease. Since the C1 esterase inhibitor (C1-INH) is a potent inhibitor of all these systems, its role in the disease has been investigated, but some issues remained unresolved. Methods: We evaluated the impact of C1-INH and KKS on disease progression in a cohort of 45 COVID-19 patients divided into groups according to disease severity. We measured plasma levels of total and functional C1-INH and its complexes with kallikrein (PKa), reflecting KKS activation and kallikrein spontaneous activity. Results: We observed increased total and functional plasma concentrations of C1-INH in COVID-19 patients. A direct correlation (positive Spearman’s r) was observed between C1-INH levels, especially functional C1-INH, and the severity of the disease. Moreover, a significant reduction in the ratio of functional over total C1-INH was evident in patients exhibiting mild to intermediate clinical severity but not in critically ill patients. Accordingly, activation of the KKS, assessed as an increase in PKa:C1-INH complexes, was explicitly observed in the mild categories. Conclusions: Our study’s findings on the consumption of C1-INH and the activation of the KKS in the less severe stages of COVID-19 but not in the critical stage suggest a potential role for C1-INH in containing disease severity. These results underscore the importance of C1-INH in the early phases of the disease and its potential implications in COVID-19 progression and/or long-term effects.