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To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein-Kinin (KKS), the Coagulation/Fibrinolysis and the Renin-Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg ]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19.

In engineering practice, additively manufactured (AM) metal and metal alloy structural components, which often contain geometric discontinuities to fulfil functional requirements, are subjected to cyclic service loads. Among the possible loading configurations, far-field Mode I loading is frequently considered as a nominal reference condition. Within this context, a methodology for the fatigue assessment of notched AM Scalmalloy components subjected to Mode I far-field loading is proposed, combining the Strain Energy Density (SED) approach with a multiaxial critical plane-based fatigue criterion. The fatigue assessment is carried out at a verification point whose position is defined as a function of the characteristic length of the SED control volume for Mode I loading, determined through two alternative procedures, and of the surface roughness of the component. The proposed methodology is validated against experimental fatigue data available in the literature for AM Scalmalloy specimens featuring a circumferential semi-circular notch and subjected to Mode I far-field cyclic loading, which induces a locally multiaxial stress state at the notch root, given that the formulation does not rely on material-specific assumptions and could in principle be extended to other notched AM metal and metal alloy components.

Attacks of hereditary angioedema (HAE) are unpredictable and, if affecting the upper airway, can be lethal. Icatibant is used for physician- or patient self-administered symptomatic treatment of HAE attacks in adults. Its mode of action includes disruption of the bradykinin pathway via blockade of the bradykinin B(2) receptor. Early treatment is believed to shorten attack duration and prevent severe outcomes; however, evidence to support these benefits is lacking. To examine the impact of timing of icatibant administration on the duration and resolution of HAE type I and II attacks. The Icatibant Outcome Survey is an international, prospective, observational study for patients treated with icatibant. Data on timings and outcomes of icatibant treatment for HAE attacks were collected between July 2009-February 2012. A mixed-model of repeated measures was performed for 426 attacks in 136 HAE type I and II patients. Attack duration was significantly shorter in patients treated <1 hour of attack onset compared with those treated ≥ 1 hour (6.1 hours versus 16.8 hours [p<0.001]). Similar significant effects were observed for <2 hours versus ≥ 2 hours (7.2 hours versus 20.2 hours [p<0.001]) and <5 hours versus ≥ 5 hours (8.0 hours versus 23.5 hours [p<0.001]). Treatment within 1 hour of attack onset also significantly reduced time to attack resolution (5.8 hours versus 8.8 hours [p<0.05]). Self-administrators were more likely to treat early and experience shorter attacks than those treated by a healthcare professional. Early blockade of the bradykinin B(2) receptor with icatibant, particularly within the first hour of attack onset, significantly reduced attack duration and time to attack resolution.

Patients affected by angioedema due to hereditary and acquired C1-inhibitor (C1-INH) deficiency (HAE and AAE, respectively) report trouble accessing dental care, due to the risk of a life-threatening oropharyngeal and laryngeal attack triggered by dental procedures. The aim of this study was to assess the identification of hurdles in receiving dental care, and the effectiveness of short-term prophylaxis (STP) in preventing angioedema attacks. In addition, the study evaluated the impact of dental care in angioedema disease. All patients affected by angioedema due to C1-INH deficiency who were treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) between 2009 and 2017 were considered for the analysis. Data were collected from patients' records. Twenty-nine patients were analyzed (27 with HAE and 2 with AAE). Of these, 63.0% reported that they had previously experienced hurdles in accessing dental care. Among patients with pathological oral status, at the first visit, 59.26% patients had moderate-to-severe oral disease. Seventy-five dental procedures were performed in 20 patients. Sixty procedures were preceded by STP (58 with plasma-derived C1-INH and 2 with danazol) in patients with/without long-term prophylaxis (LTP). Post-procedural attacks occurred in two patients. One HAE patient undergoing a tooth extraction without STP/LTP experienced a laryngeal attack. The other post-procedural attack occurred in an AAE patient with anti-C1-INH antibodies with STP with pdC1-INH. The angioedema disease did not worsen in any patient after dental care, but improved in four of them. Most C1-INH-HAE patients reported hurdles in receiving dental care. STP protects against attacks after dental procedures. Treating oral diseases results in improvement in the frequency of attacks.

Background Hereditary angioedema with C1 inhibitor deficiency is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. Self-treatment is recommended, in order to reduce admissions to the Emergency Room and the time between the onset of the attack and the treatment, resulting in a better treatment outcome and an improved quality of life (QoL). The purpose of this study is to assess the safety, tolerability, and effect on QoL of self-administration of pnf C1-INH for IV use (Berinert®). Methods An observational, monocenter, prospective study was designed. Patients referring to a center for angioedema that attended two sessions of self-infusion training course in the period March 2014–July 2015 were enrolled in the study. The primary endpoint was to monitor the safety and feasibility of pnf C1-INH self-infusion. The secondary endpoint was to evaluate the effect of self-infusion on the QoL, by means of the HAE-QoL questionnaire and the need for access to Emergency Room for infusion of Berinert®. Patients’ medical history data were collected upon the first visit and questionnaires were filled after each attack treated with Berinert® (diary and Treatment Satisfaction Questionnaire for Medication ) and upon the first visit and the follow-ups (HAE-QoL). Results Twenty patients were enrolled (median age = 42, IQR: 39–49; 60% females). Fifteen patients completed the study. A total of 189 attacks were recorded (annual median rate of 4 attacks/patient). Patients waited a median of 2 h (IQR: 1–4) before self-administration, and the resolution of the attack occurred after a median of 6 h (IQR: 4–11). Most attacks were abdominal (39%) and peripheral (22%). 92% of the attacks were treated through self−/caregiver-administration. In most attacks no side effects were reported. The number of attacks with side effects decreased over time, from 37% to 13%. Global satisfaction grew over time during the study period, reaching statistical significance over the first 6 months. The median total HAE-QoL score at baseline was 86 (IQR: 76–103) and improved in a non-significant manner throughout the study period. 8% of the attacks treated with Berinert® required ER admission/healthcare professional help in the study period, compared with 100% in the 3 years before enrollment ( p  < 0.0001). Conclusions Self-administration of pnf C1-INH is safe, and increases patients’ confidence in the treatment, showing also a trend towards an improvement in QoL. It reduces the need for ER admission/healthcare professionals help for the acute attacks, as well as the related costs.

Background Hereditary angioedema (HAE) adversely affects health-related quality of life (HRQoL). HAE often compromises the HRQoL due to the impact on functional capacity caused by edema, pain, other symptoms, and psychosocial factors. Patient-Reported Outcome Measures (PROMs) focus on HRQoL and are crucial tools for evaluating the burden of the disease and choosing the most appropriate interventions for this population. However, no comprehensive evaluations of the characteristics of the available measurements to assess HRQoL have been conducted for this population. Aim To identify, analyze, and summarize the PROMs assessing HRQoL in individuals with HAE-C1-INH, addressing the gap in standardized assessment tools. Methods A systematic review was conducted up to December 2023 in PubMed, Scopus, Web of Science, Embase, and CINAHL databases, following PRISMA guidelines without language or time restrictions. Psychometric properties of the identified PROMs were appraised using COSMIN standards, and evidence was synthesized using a modified GRADE approach. Results From seven studies, five HRQoL PROMs were identified: two generic (SF-36 and SF-36v2) and three disease-specific (HAE-QoL, HAEA-QoL, and AE-QoL). These PROMs generally lacked comprehensive content, structural and cross-cultural validation, with none meeting the criteria for measurement invariance. This limitation affects their applicability across different demographics and cultures. However, the HAE-QoL and AE-QoL instruments were recognized for having moderate quality evidence, suggesting their potential reliability and validity. Conclusions This systematic review provides a moderate recommendation for the use of HAE-QoL and AE-QoL in assessing HRQoL in adults with HAE. Despite identified gaps, the moderate evidence quality for these tools supports their use, pending further validation, involving younger age groups and disease-specific contents in the assessments. Developing culturally and demographically adaptable PROMs is, therefore, a priority to improve the accuracy of PROMs in this field. Review registration number PROSPERO registration number is CRD42023440137.

Angioedema due to acquired C1 inhibitor deficiency (AAE-C1INH) is a rare, serious condition that manifests with recurring and often painful swelling attacks. No approved treatments or validated patient-reported outcome (PRO) measures exist for AAE-C1INH. This study aimed to develop a conceptual model of AAE-C1INH and explored the relevance of adapting PRO measures validated for hereditary angioedema, another bradykinin-mediated disease. This cross-sectional, qualitative study involved semi-structured interviews with 8 adults living with AAE-C1INH. Open-ended questions elicited participants' descriptions of AAE-C1INH manifestations and daily life impacts. Cognitive interviews assessed perceptions of clarity, comprehension, and meaningful levels of change in PRO measures: Patient Global Impression of Change (PGI-C) and Severity (PGI-S) and Patient Global Assessment of Status (PGA-S) and Change (PGA-C). Participants reported traumatic medical emergencies, misdiagnoses, and evaluations by a variety of healthcare providers. Daily life impact was common (social/family and treatment-related; n=7). Attack areas most frequently reported were abdomen (n=7), face (n=6), and foot/hand (n=5 each). Evaluating PGI-C, 8/8 participants correctly interpreted the scale to assess symptoms at a given time post-treatment vs. at time of treatment for a theoretical AAE-C1INH attack. Four of 8 participants considered \"a little better\" ≥2 hours post-treatment and 6/6 considered \"better\" ≥4 hours as meaningful. Most also considered PGI-S and PGA easy to interpret and relevant to their symptoms. Interviews highlighted the impact of AAE-C1INH on participants' lives and overall well-being. Participants' assessments of PRO items have informed the clinical outcome assessment strategy for the first phase 3 clinical trial exclusively in AAE-C1INH.

Randomized controlled trial data for non-histaminergic normal C1 inhibitor (nC1INH) angioedema prevention are lacking. Patients aged ≥12 years with investigator-confirmed non-histaminergic nC1INH angioedema were enrolled in phase III, multicenter, randomized, placebo-controlled, double-blind CASPIAN Study (NCT04206605). Patients with ≥1 investigator-confirmed angioedema attack/4 weeks during observation period were randomized 2:1 to lanadelumab 300 mg every 2 weeks or placebo. Primary efficacy outcome was investigator-confirmed angioedema attack number during the 26-week treatment period. Safety was analyzed as treatment-emergent adverse events (TEAEs). After completing the treatment period, patients could roll over to CASPIAN open-label extension (CASPIAN OLE; NCT04444895) for an additional 26-week lanadelumab treatment to assess long-term safety and efficacy. A total of 77 patients (mean ± SD age of 42.8 ± 12.9 years, 80.5% women, 88.3% White) were enrolled (lanadelumab, 50; placebo, 27). Primary efficacy outcome was not different with lanadelumab versus placebo (1.82 vs. 1.78 attacks/month; rate ratio, 1.02; p=0.90), with attack rate reduction from baseline in both groups. Subgroups meeting a clinical definition of HAE [known mutations (n=5) or family history and unknown mutations (n=13)] showed positive attack rate reduction trend with lanadelumab versus placebo. Angioedema attack rate reduction with lanadelumab was observed in CASPIAN OLE. In both studies, all treatment-related TEAEs were non-serious, and most were non-severe; most frequent treatment-related TEAEs were similar to those previously reported in lanadelumab clinical trials. In patients with non-histaminergic nC1INH angioedema, lanadelumab safety was consistent with previous studies; efficacy remained inconclusive due to unmet CASPIAN primary endpoint. Overall results suggest potential clinical benefit in symptom control. https://www.clinicaltrials.gov/, identifiers NCT04206605, NCT04444895.

Hereditary angioedema (HAE) is a rare, unpredictable disease that imposes a substantial and multifaceted burden on patients' daily lives, with many not achieving the World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) recommended treatment goal of normalisation of life. In March 2025, a European expert committee convened to discuss how to effectively implement WAO/EAACI guidelines in clinical practice, identifying a Treat-to-Target (T2T) approach to support consistent adoption of guideline recommendations into routine care. Through iterative expert discussion and consensus, a T2T algorithm was developed to support the achievement of optimal treatment goals for adolescents and adults with HAE, providing a structured, patient-centred strategy to guide HAE management. Feasibility and clarity of the consensus T2T algorithm were evaluated via an online survey of 64 European clinicians and 15 representatives from patient organisations. Feedback from the survey was used to refine the final version. The T2T algorithm provides a visual, practical framework that offers guidance on initiating long-term prophylaxis (LTP), as well as setting and assessing individualised short- and long-term targets and treatment plans. Target attainment is achieved through regular monitoring, involving a comprehensive assessment of disease activity and burden, analysis of the causes of breakthrough attacks, and considering optimising management or switching LTP treatment when targets are not being reached. The ultimate goal of treatment for HAE is to achieve normalisation of life. By setting clear, measurable, and individualised treatment targets supported by shared decision-making, regular monitoring and treatment optimisation as needed, this consensus-derived T2T algorithm aims to promote more consistent care within the HAE community and ultimately improve patient outcomes.

Introduction Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE type I) or dysfunction (C1-INH-HAE type II) is a rare disease characterized by recurrent episodes of edema with an estimated frequency of 1:50,000 in the global population without racial or gender differences. In this study we present the results of a nationwide survey of C1-INH-HAE patients referring to 17 Italian centers, the Italian network for C1-INH-HAE, ITACA. Methods Italian patients diagnosed with C1-INH-HAE from 1973 to 2013 were included in the study. Diagnosis of C1-INH-HAE was based on family and/or personal history of recurrent angioedema without urticaria and on antigenic and/or functional C1-INH deficiency. Results 983 patients (53% female) from 376 unrelated families were included in this survey. Since 1973, 63 (6%) patients diagnosed with C1-INH-HAE died and data from 3 patients were missing when analysis was performed. Accordingly, the minimum prevalence of HAE in Italy in 2013 is 920:59,394,000 inhabitants, equivalent to 1:64,935. Compared to the general population, patients are less represented in the early and late decades of life: men start reducing after the 5 th decade and women after the 6 th . Median age of patients is 45 (IQ 28-57), median age at diagnosis is 26 years (IQ 13-41). C1-INH-HAE type 1 are 87%, with median age at diagnosis of 25 (13-40); type 2 are 13% with median age at diagnosis of 31 (IQ 16-49). Functional C1INH is ≤50% in 99% of patients. Antigen C1INH is ≤50% in 99% of type 1. C4 is ≤50% in 96% of patients. The chance of having C1-INH-HAE with C4 plasma levels >50% is < 0.05. Conclusion This nationwide survey of C1-INH-HAE provides for Italy a prevalence of 1:64,935. C1-INH-HAE patients listed in our database have a shorter life expectancy than the general population. An increased awareness of the disease is needed to reduce this discrepancy. Measurement of C4 antigen can exclude diagnosis of C1-INH-HAE with an accuracy > 95%. This parameter should be therefore considered for initial screening in differential diagnosis of angioedema.