55,714 research outputs found
The UN-SUSTAINABLE Match in HCV Recipients. Evidences from the Italian D-MELD Study on Balancing Donor-Recipient Risk Factors
No full textThe UN-SUSTAINABLE Match in HCV Recipients. Evidences from the Italian D-MELD Study on Balancing Donor-Recipient Risk Factor
261st ENMC International Workshop: management of safety issues arising following AAV gene therapy. 17th-19th June 2022, Hoofddorp, The Netherlands
No full textAdeno-associated virus (AAV) gene therapies are demonstrating much promise in the area of neuromuscular disorders. There are now therapies in clinical trials or real-world use for several disorders including spinal muscular atrophy and Duchenne muscular dystrophy. However, there have been several concerning reports of serious adverse events, including deaths. Reporting and monitoring of these is not consistent between trials. Therefore, a group of clinicians, investigators, industry and patient representatives met the weekend of 17th–19th June 2022 to discuss safety issues arising from the use of these therapies. The group shared information on safety events across a spectrum of AAV gene therapy products, both in clinical trials and commercial use. Patterns of serious adverse events were identified and the group discussed methods of identification and management of these as well as new ways of improving information sharing across industry in order to improve the safety of these promising treatments
Validation of the Italian version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire
No full textObjectives: The primary objective of this study was the translation and validation of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire into Italian, denoted as AAV-PRO_ita. The secondary objective was to evaluate the impact of ANCA-associated vasculitis (AAV) on quality of life (QoL) and work impairment in a large cohort of Italian patients. Methods: The study design took a prospective cohort study approach. First, the AAV-PRO was translated into Italian following the step guidelines for translations. The new AAV-PRO_ita questionnaire covered three disease domains: organ-specific and systemic symptoms and signs; physical function; and social and emotional impact. Second, Italian-speaking AAV patients were recruited from 17 Italian centres belonging to the Italian Vasculitis Study Group. Participants completed the AAV-PRO_ita questionnaire at three time points. Participants were also requested to complete the work productivity and activity impairment: general health questionnaire. Results: A total of 276 AAV patients (56.5% women) completed the questionnaires. The AAV-PRO_ita questionnaire demonstrated a good internal consistency and test–retest reliability. Female AAV patients scored higher (i.e. worse) in all thee domains, especially in the social and emotional impact domain (P < 0.001). Patients on glucocorticoid therapy (n 1⁄4 199) had higher scores in all domains, especially in the physical function domain (P < 0.001), compared with patients not on glucocorticoid therapy (n 1⁄4 77). Furthermore, patients who had at least one relapse of disease (n 1⁄4 114) had higher scores compared with those who had never had one (n 1⁄4 161) in any domain (P < 0.05). Finally, nearly 30% of the patients reported work impairment. Conclusion: The AAV-PRO_ita questionnaire is a new 29-item, disease-specific patient-reported outcome measuring tool that can be used in AAV research in the Italian language. Sex, glucocorticoids and relapsing disease showed the greatest impact on QoL
Efficacy and safety of Extended-Interval Rituximab vs. Standard MAINRITSAN Regimen for remission Maintenance in ANCA-Associated Vasculitis: A Multicenter Study
No full textreservedBackground: Rituximab (RTX) achieved high remission-induction and sustained maintenance rates for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [1,2]. However, RTX is an expensive medication, which may potentially lead to serious side effects. Defining the best dose regimen for maintenance in AAV is still an unmet need.
Objectives: The aim of the present study is to compare the effects of extended interval of RTX (500 mg once per year) to standard MAINRITSAN regimen RTX (500 mg twice per year) as remission-maintenance therapy in AAV patients.
Methods: We included consecutive AAV patients (classified as GPA and MPA) referring to four different Rheumatology centers in Italy. We assessed AAV patients who successfully achieved disease remission (BVASv3=0) with conventional RTX or others immunosuppressive regimens and have been subsequently treated with RTX for maintenance of remission. Maintenance regimens were classifies according to the timing of RTX administration, in the MAINRITSAN maintenance group (RTX 500-mg at six-month intervals) and thee Extended-Interval group (RTX 500 mg once a year). Some patients started maintenance with Extended-interval regimen, while others switched to the annual regimen during the course of standard six-monthly maintenance. After at least two consecutive infsione, we assessed the remission rate, damage, glucocorticoids intake, ANCA status, serum immunoglobulin levels, infections and deaths.
Results: From October 2011 to October 2024, 100 AAV patients (median age 60 [54-70], 54% female, 97% ANCA positive, 67% anti PR3), 65 classified as GPA and 25 MPA, achieved complete disease remission with conventional RTX induction regimen. Between them 82 started maintenance with standard regimen and 18 with Extended- interval. Among MAINRITSAN group, 29 patients switched to 12-months scheme. No significant differences at baseline were noted between groups. At the end of observation period relapse rate, infection incidence and deaths were comparable between the two group. No differences were noted in remission maintenance, negative ANCA negativization and glucocorticoid discontinuation at last follow-up.
Conclusions: Reduced exposure to RTX was not associated with an impaired efficacy of maintenance therapy in patients with AAV. Remission maintenance with extended-interval of RTX is a safe and more cost-effective option
All repair and reconstruction. Techniques from the SANTI study group
No full textBackground: Combining an anterior cruciate ligament (ACL) reconstruction with an anterolateral ligament (ALL) reconstruction results in significant advantages including reduced graft rupture rates, a lower risk of reoperation for secondary meniscectomy, improved knee stability, and higher rates of return to preinjury levels of sport. Indications: The previously reported indications for combined ACL and ALL reconstruction are as follows: ACL reconstruction revision; high-grade pivot shift test; long-term ACL rupture; young patients; pivoting activities; concomitant medial meniscus repair, and, specifically, regarding the ALL repair, it must be an acute surgery (within 15 days from injury). Technique Description: Several modern techniques have been described to repair and reconstruct the ALL. This technical note details a number of these techniques performed by the Scientific Anterior Cruciate Ligament Network International (SANTI) Study Group. Results: First, we describe a combined ACL reconstruction and double-bundle ALL reconstruction using hamstring autograft. Secondly, we describe a single-bundle ALL reconstruction using gracilis autograft. Thirdly, we describe an ALL reconstruction technique using a knotless soft anchor, which provides shallow fixation and prevents tunnel convergence. Finally, we describe a technique for ALL repair. Conclusion: Several techniques have been described to repair and reconstruct the ALL, all offering significant advantages over an isolated ACL reconstruction. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication
Robust automated detection of microstructural white matter degeneration in Alzheimer’s disease using machine learning classification of multicenter DTI data
No full textDiffusion tensor imaging (DTI) based assessment of white matter fiber tract integrity can support the diagnosis of Alzheimer’s disease (AD). The use of DTI as a biomarker, however, depends on its applicability in a multicenter setting accounting for effects of different MRI scanners. We applied multivariate machine learning (ML) to a large multicenter sample from the recently created framework of the European DTI study on Dementia (EDSD). We hypothesized that ML approaches may amend effects of multicenter acquisition. We included a sample of 137 patients with clinically probable AD (MMSE 20.6±5.3) and 143 healthy elderly controls, scanned in nine different scanners. For diagnostic classification we used the DTI indices fractional anisotropy (FA) and mean diffusivity (MD) and, for comparison, gray matter and white matter density maps from anatomical MRI. Data were classified using a Support Vector Machine (SVM) and a Naïve Bayes (NB) classifier. We used two cross-validation approaches, (i) test and training samples randomly drawn from the entire data set (pooled cross-validation) and (ii) data from each scanner as test set, and the data from the remaining scanners as training set (scanner-specific cross-validation). In the pooled cross-validation, SVM achieved an accuracy of 80% for FA and 83% for MD. Accuracies for NB were significantly lower, ranging between 68% and 75%. Removing variance components arising from scanners using principal component analysis did not significantly change the classification results for both classifiers. For the scanner-specific cross-validation, the classification accuracy was reduced for both SVM and NB. After mean correction, classification accuracy reached a level comparable to the results obtained from the pooled cross-validation. Our findings support the notion that machine learning classification allows robust classification of DTI data sets arising from multiple scanners, even if a new data set comes from a scanner that was not part of the training sample
Effectiveness of brief schema group therapy for borderline personality disorder symptoms : a randomized pilot study
No full textBackground and objectives Schema group therapy is a potentially cost-effective treatment for borderline personality disorder (BPD). We piloted the feasibility and effectiveness of a 20-session schema group therapy without individual therapy among psychiatric BPD outpatients in a randomized pilot study registered as a clinical trial (ISRCTN76381242). Methods Altogether 42 psychiatric outpatients diagnosed with BPD were randomized 2:1 to a 20-session weekly schema group therapy plus treatment as usual (TAU) (n = 28) vs. a control group with TAU alone (n = 14). The primary outcome was decline of BPD symptoms in the short Borderline Symptom List (BSL-23) score. Secondary outcomes were decline in symptoms of anxiety, depression, alcohol use, and improvement in functioning and schema modes. Two external experts evaluated validity of the intervention based on videotaped sessions. Results Overall, 23 schema group therapy patients (82%) and 12 controls (86%) completed their treatment. Treatment validity good or very good. However, no significant differences emerged in the primary outcome mean BSL-23 decline (6.95 [SE 5.91] in group schema therapy vs. 12.55 [4.85] in TAU) or in any of the secondary outcome measures. Limitations Despite randomization, the TAU subgroup had non-significantly higher baseline scores in most measures. Small sample size predisposing to type II errors; reliance on self-reported outcomes. Conclusions Schema group therapy was feasible for psychiatric outpatients with BPD. However, in this small pilot study we did not find it more effective than TAU. Effectiveness of this short intervention remains open.Peer reviewe
Pulse oximetry adoption and oxygen orders at paediatric admission over 7 years in Kenya: a multihospital retrospective cohort study
No full textObjectives To characterise adoption and explore specific clinical and patient factors that might influence pulse oximetry and oxygen use in low-income and middle-income countries (LMICs) over time; to highlight useful considerations for entities working on programmes to improve access to pulse oximetry and oxygen.
Design A multihospital retrospective cohort study.
Settings All admissions (n=132 737) to paediatric wards of 18 purposely selected public hospitals in Kenya that joined a Clinical Information Network (CIN) between March 2014 and December 2020.
Outcomes Pulse oximetry use and oxygen prescription on admission; we performed growth-curve modelling to investigate the association of patient factors with study outcomes over time while adjusting for hospital factors.
Results Overall, pulse oximetry was used in 48.8% (64 722/132 737) of all admission cases. Use rose on average with each month of participation in the CIN (OR: 1.11, 95% CI 1.05 to 1.18) but patterns of adoption were highly variable across hospitals suggesting important factors at hospital level influence use of pulse oximetry. Of those with pulse oximetry measurement, 7% (4510/64 722) had hypoxaemia (SpO2 <90%). Across the same period, 8.6% (11 428/132 737) had oxygen prescribed but in 87%, pulse oximetry was either not done or the hypoxaemia threshold (SpO2 <90%) was not met. Lower chest-wall indrawing and other respiratory symptoms were associated with pulse oximetry use at admission and were also associated with oxygen prescription in the absence of pulse oximetry or hypoxaemia.
Conclusion The adoption of pulse oximetry recommended in international guidelines for assessing children with severe illness has been slow and erratic, reflecting system and organisational weaknesses. Most oxygen orders at admission seem driven by clinical and situational factors other than the presence of hypoxaemia. Programmes aiming to implement pulse oximetry and oxygen systems will likely need a long-term vision to promote adoption, guideline development and adherence and continuously examine impact
Perinatal Gene Transfer to the Liver
No full textThe liver acts as a host to many functions hence raising the possibility that any one may be compromised by a single gene defect.
Inherited or de novo mutations in these genes may result in relatively mild diseases or be so devastating that death within the first
weeks or months of life is inevitable. Some diseases can be managed using conventional medicines whereas others are, as yet, untreatable.
In this review we consider the application of early intervention gene therapy in neonatal and fetal preclinical studies. We appraise
the tools of this technology, including lentivirus, adenovirus and adeno-associated virus (AAV)-based vectors. We highlight the application
of these for a range of diseases including hemophilia, urea cycle disorders such as ornithine transcarbamylase deficiency, organic
acidemias, lysosomal storage diseases including mucopolysaccharidoses, glycogen storage diseases and bile metabolism. We conclude by
assessing the advantages and disadvantages associated with fetal and neonatal liver gene transfer
a European multicenter comparative cohort study
No full textFunding Information: AR received personal fees from Maat Pharma, IML received personal fees from MSD, and Gilead. AA received personal fees from Lilly Foundation, and grants from Grifols and Fisher & Paykel. CEL received personal fees from Bayer, Merck, Aerogen, Biomérieux, ThermoFisher Brahms, and Carmat. SN received personal fees from MSD, Bio-Rad, BioMérieux, Gilead, Fisher and Paykel, and Pfizer. All other authors declare no competing interests. Funding Information: This study was supported in part by a grant from the French government through the « Programme Investissement d’Avenir» (I-SITE ULNE) managed by the Agence Nationale de la Recherche (coVAPid project). Prof. Ignacio Martin-Loeches has been supported by SFI (Science Foundation Ireland), Grant Number 20/COV/0038. The funders of the study had no role in the study design, data collection, analysis, or interpretation, writing of the report, or decision to submit for publication. Publisher Copyright: © 2022, The Author(s).Background: Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients. Objectives: To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients. Methods: This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event. Results: A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53–7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88–5.46, p < 0.0001). In the whole study population, putative IPA was associated with significant increase in 28-day mortality rate, and length of ICU stay, compared with colonized patients, or those with no IPA or Aspergillus colonization. Conclusions: Overall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693.publishersversionpublishe
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