Idiopathic pulmonary fibrosis (IPF) is a chronic disease with unknown etiology and poor prognosis. Little is known about the epidemiology of this disease; most of the studies are limited by small and ...restricted cohort studies. We aim to investigate the epidemiology of IPF in the Italian primary care setting using the Health Search Database (HSD) between January 2002 and June 2017. In an attempt to define cases of IPF we adopted iterative combinations of International Classification of Diseases Ninth Revision (ICD-9-CM) and other clinical investigations according to three different operational Algorithms. Incidence and prevalence rate, according to the three Algorithms defining IPF, were calculated and the association with candidate determinants sex, age, gastro-esophageal reflux (GERD) and smoking status was evaluated. We identified 1,104,307 eligible patients. The prevalence rate of IPF varies between 2.6 to 24.3 per 100.000 person-year, using algorithm 1 and from 0.8 to 7 using algorithm 3. The incidence rate of IPF varies between 1.25 and 3.77 per 100.000 person-years, using algorithm 1 and from 0.10 to 1.61 using algorithm 3. The mean adjusted incidence rate ratio of IPF, using algorithm 1, is 2.33 (95% CI 2.11–2.57) per 100.000 person-years. Over the study years, the trend of prevalence was statistically significantly increasing while the incidence rate started to increase in the last 3 years. The analyses on candidate determinants showed that patients aged 61 years or older, those suffering from GERD, and former smokers were statistically significantly at greater risk of incurring IPF. To our knowledge, this is one of the first European IPF epidemiological studies conducted in primary care. The increase of the incidence rates is likely due to a growing awareness for IPF among General Practitioners, while the increase of prevalence rates may be due to an increase of survival, a result of recent advances in the diagnosis, management and therapies for the disease.
It is known from previous literature that type II Spinal Muscular Atrophy (SMA) patients generally, after the age of 5 years, presents a steep deterioration until puberty followed by a relative ...stability, as most abilities have been lost. Although it is possible to identify points of slope indicating early improvement, steep decline and relative stabilizations, there is still a lot of variability within each age group and it's not always possible to predict individual trajectories of progression from age only. The aim of the study was to develop a predictive model based on machine learning using an XGBoost algorithm for regression and report, explore and quantify, in a single centre longitudinal natural history study, the influence of clinical variables on the 6/12-months Hammersmith Motor Functional Scale Expanded score prediction (HFMSE). This study represents the first approach to artificial intelligence and trained models for the prediction of individualized trajectories of HFMSE disease progression using individual characteristics of the patient. The application of this method to larger cohorts may allow to identify different classes of progression, a crucial information at the time of the new commercially available therapies.
Background:
No uniform criteria for a sensitive identification of the transition from relapsing–remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available.
...Objective:
To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA).
Methods:
Relapsing-onset MS patients (n = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models.
Results:
SPMS identified by the DDA (n = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability (p < 0.0001), than those identified by the ND (n = 3868, 20.0%). In both groups, the most consistent risk factors (p < 0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0.
Conclusion:
A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.
There is currently limited evidence on the level and intensity of physical activity in individuals with hemophilia A. Mobile technologies can offer a rigorous and reliable alternative to support data ...collection processes but they are often associated with poor user retention. The lack of longitudinal continuity in their use can be partly attributed to the insufficient consideration of stakeholder inputs in the development process of mobile apps. Several user-centered models have been proposed to guarantee that a thorough knowledge of the end user needs is considered in the development process of mobile apps.
The aim of this study is to design and validate an electronic patient-reported outcome mobile app that requires sustained active input by individuals during POWER, an observational study that aims at evaluating the relationship between physical activity levels and bleeding in patients with hemophilia A.
We adopted a user-centered design and engaged several stakeholders in the development and usability testing of this mobile app. During the concept generation and ideation phase, we organized a need-assessment focus group (FG) with patient representatives to elicit specific design requirements for the end users. We then conducted 2 exploratory FGs to seek additional inputs for the app's improvement and 2 confirmatory FGs to validate the app and test its usability in the field through the mobile health app usability questionnaire.
The findings from the thematic analysis of the need-assessment FG revealed that there was a demand for sense making, for simplification of app functionalities, for maximizing integration, and for minimizing the feeling of external control. Participants involved in the later stages of the design refinement contributed to improving the design further by upgrading the app's layout and making the experience with the app more efficient through functions such as chatbots and visual feedback on the number of hours a wearable device had been worn, to ensure that the observed data were actually registered. The end users rated the app highly during the quantitative assessment, with an average mobile health app usability questionnaire score of 5.32 (SD 0.66; range 4.44-6.23) and 6.20 (SD 0.43; range 5.72-6.88) out of 7 in the 2 iterative usability testing cycles.
The results of the usability test indicated a high, growing satisfaction with the electronic patient-reported outcome app. The adoption of a thorough user-centered design process using several types of FGs helped maximize the likelihood of sustained retention of the app's users and made it fit for data collection of relevant outcomes in the observational POWER study. The continuous use of the app and the actual level of engagement will be evaluated during the ongoing trial.
ClinicalTrials.gov NCT04165135; https://clinicaltrials.gov/ct2/show/NCT04165135.
Human monoclonal antibodies (mAbs) can routinely be isolated from phage display libraries against virtually any protein available in sufficient purity and quantity, but library design can influence ...epitope coverage on the target antigen. Here we describe the construction of a novel synthetic human antibody phage display library that incorporates hydrophilic or charged residues at position 52 of the CDR2 loop of the variable heavy chain domain, instead of the serine residue found in the corresponding germline gene. The novel library was used to isolate human mAbs to various antigens, including the alternatively-spliced EDA domain of fibronectin, a marker of tumor angiogenesis. In particular, the mAb 2H7 was proven to bind to a novel epitope on EDA, which does not overlap with the one recognized by the clinical-stage F8 antibody. F8 and 2H7 were used for the construction of chelating recombinant antibodies (CRAbs), whose tumor-targeting properties were assessed in vivo in biodistribution studies in mice bearing F9 teratocarcinoma, revealing a preferential accumulation at the tumor site.
In many passages of his works, John Tzetzes likens himself to different figures from the Greek and Roman past in order to emphasise relevant features of his authorial persona. This strategy has been ...the subject of recent studies, which underscore the self-advertising agenda underlying Tzetzes’ constant reference to – and identification with – Greek and Roman models. Drawing on and going beyond this strand of literature, this paper pursues two main goals. First, it aims to situate Tzetzes’ references to these figures from the past within the broader sociocultural dynamics informing his self-fashioning strategy. To this end, it will focus on passages of his works dealing with friendship and patronage, two social practices that were crucial to any Byzantine writer. Second, the paper seeks to show that Tzetzes uses these figures to reflect upon his condition as a commissioned writer, skilfully employing them to create an authorial narrative that both spells out and plays with the constraints and contradictions stemming from his professional status.
In many passages of his works, John Tzetzes likens himself to different figures from the Greek and Roman past in order to emphasise relevant features of his authorial persona. This strategy has been ...the subject of recent studies, which underscore the self-advertising agenda underlying Tzetzes’ constant reference to – and identification with – Greek and Roman models. Drawing on and going beyond this strand of literature, this paper pursues two main goals. First, it aims to situate Tzetzes’ references to these figures from the past within the broader sociocultural dynamics informing his self-fashioning strategy. To this end, it will focus on passages of his works dealing with friendship and patronage, two social practices that were crucial to any Byzantine writer. Second, the paper seeks to show that Tzetzes uses these figures to reflect upon his condition as a commissioned writer, skilfully employing them to create an authorial narrative that both spells out and plays with the constraints and contradictions stemming from his professional status.
Abstract
Background
Spinal muscular atrophy (SMA) is a rare genetic disease with a broad spectrum of severity. Although an early diagnosis of SMA is crucial to allow proper management of patients, ...the diagnostic delay is still an issue. Therefore, this study aimed to investigate the clinical correlates of SMA among primary care patients.
Methods
The Health Search Database (HSD) was adopted. To estimate the prevalence and incidence rate of SMA, a cohort study was conducted on the population (aged ≥6 years) being registered in HSD from 1 January 2000 up to 31 December 2019. To investigate the clinical correlates of SMA, a nested case–control study was performed. SMA cases have been classified according to a clinically based iterative process as “certain”, “probable” or “possible”. To test the association between clinical correlates and SMA cases a multivariate conditional logistic regression model was estimated.
Results
The SMA prevalence combining “certain”, “probable” and “possible” cases was 5.1 per 100,000 in 2019 (i.e. 1.12 per 100,000 when limited to “certain” cases), while the yearly incidence rate ranged from 0.12 to 0.56 cases per 100,000. Comparing “certain” cases with matched controls, the presence of neurology visits (OR = 6.5; 95% CI: 1.6–25.6) and prescription of electromyography (OR = 4.6; 95% CI: 1.1–18.7) were associated with higher odds of SMA diagnosis.
Conclusions
Our findings suggest that primary care databases may be used to enhance the early identification of SMA. Additional efforts are needed to exploit the electronic health records of general practitioners to allow early recognition of SMA.
The aim of this study was to estimate primary care costs of prodromal signs/symptoms of Alzheimer disease (AD), during a 10-year or longer period preceding AD diagnosis, in relation to costs ...cumulated in the general population for the same reasons.
Nested case-control study involving 1889 AD cases and 18,890 controls aged 60+ from the Italian primary care Health Search Database (HSD). AD incident cases were through the International Classification of Diseases, 9th edition. Costs related to drugs, diagnostic tests and specialist referrals triggered by prodromal AD signs and/or symptoms were quantified and compared with costs cumulated by non-AD counterparts.
During the pre-diagnosis 10-year or longer period, prodromal signs and symptoms trigger diagnostic and therapeutic costs 55% higher than those cumulated in general population for the same clinical reasons. After accounting for patients' comorbidity and regional differences, the mean cost related to diagnostic and therapeutic procedures, and those related to specialist referrals, amounted to 854.1 €(SD: 630.6 €) in AD incident cases vs. 527.3 €(SD: 446.2) cumulated in patients not developing AD.
Prodromal AD manifestations are associated with primary care costs that resulted higher than those cumulated in the general population aged 60+. It remains to be elucidated if earlier dementia diagnoses would be associated with reduced costs triggered by the same clinical signs and symptoms.
L19-IL2 is an immunocytokine composed of an antibody fragment specific to the EDB domain of fibronectin, a tumor angiogenesis marker, and of human interleukin-2 (IL2). L19-IL2 delivers IL2 to the ...tumor site exploiting the selective expression of EDB on newly formed blood vessels. Previously, the recommended dose of L19-IL2 monotherapy was defined as 22.5 million international units (Mio IU) IL2 equivalents. In this study, safety and clinical activity of L19-IL2 in combination with dacarbazine were assessed in patients with metastatic melanoma.
The first 10 studied patients received escalating doses of L19-IL2 on days 1, 3, and 5 in combination with 1 g/m(2) of dacarbazine on day 1 of a 3-weekly therapy cycle. Subsequently, 22 patients received L19-IL2 at recommended dose plus dacarbazine. Up to six treatment cycles were given, followed by a maintenance regimen with biweekly L19-IL2.
The recommended dose of L19-IL2 in combination with dacarbazine was defined as 22.5 Mio IU. Toxicity was manageable and reversible, with no treatment-related deaths. Twenty-nine patients were evaluable for efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST). In a centralized radiology analysis, eight of 29 (28%) patients achieved a RECIST-confirmed objective response, including a complete response still ongoing 21 months after treatment beginning. The 12-month survival rate and median overall survival of the recommended dose-treated patients (n = 26) were 61.5% and 14.1 months, respectively.
The repeated administration of L19-IL2 in combination with dacarbazine is safe and shows encouraging signs of clinical activity in patients with metastatic melanoma. This combination therapy is currently evaluated in a randomized phase II trial with patients with metastatic melanoma.
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